Is it time for a retinoic acid-eluting stent or retinoic acid-coated balloon? Insights from experimental studies of systemic and local delivery of retinoids.

Although the incidence of restenosis and stent thrombosis has substantially declined during the last decades, they still constitute the two major causes of stent failure. These complications are partially attributed to the currently used cytostatic drugs, which can cause local inflammation, delay or prevent re-endothelialization and essentially cause arterial cell toxicity. Retinoic acid (RA), a vitamin A (retinol) derivative, is a naturally occurring substance used for the treatment of cell proliferation disorders. The agent has pleiotropic effects on vascular smooth muscle cells and macrophages: it influences the proliferation, migration, and transition of smooth muscle cells to other cell types and modulates macrophage activation. These observations are supported by accumulated evidence from in vitro and in vivo experiments. In addition, systemic and topical administration of RA can decrease the development of atherosclerotic plaques and reduce or inhibit restenosis after vascular injury (caused by embolectomy, balloon catheters, or ligation of arteries) in various experimental models. Recently, an RA-drug eluting stent (DES) has been tested in an animal model. In this review, we explore the effects of RA in atherosclerosis and the potential of the local delivery of RA through an RA-DES or RA-coated balloon for targeted therapeutic percutaneous vascular interventions. Despite promising published results, further experimental study is warranted to examine the safety and efficacy of RA-eluting devices in vascular artery disease.

Cleverballoon: An integrated approach for developing a drug-coated balloon with everolimus.

Coronary artery disease (CAD) is a chronic disease associated with high mortality and morbidity. Although treatment with drug-eluting stents is the most frequent interventional approach for coronary artery disease, drug-coated balloons (DCBs) constitute an innovative alternative, especially in the presence of certain anatomical conditions in the local coronary vasculature. DCBs allow the fast and homogenous transfer of drugs into the arterial wall, during the balloon inflation. Their use has been established for treating in-stent restenosis caused by stent implantation, while recent clinical trials have shown a satisfactory efficacy in de novo small-vessel disease. Several factors affect DCBs performance including the catheter design, the drug dose and formulation. Cleverballoon focuses on the design and development of an innovative DCB with everolimus. For the realization of the development of this new DCB, an integrated approach, including in- vivo, in-vitro studies and in-silico modelling towards the DCB optimization, is presented.Clinical Relevance-The proposed study introduces the integration of in- vivo, in-vitro and in silico approaches in the design and development process of a new DCB, following the principles of 3R's for the replacement, reduction, and refinement of animal and clinical studies.

Safety and Efficacy of an Innovative Everolimus-Coated Balloon in a Swine Coronary Artery Model.

BACKGROUND: Drug-coated balloons have been used as a non-stenting treatment in coronary and peripheral artery disease. Until recently, only sirolimus- and paclitaxel-coated balloons have been investigated in clinical trials. We evaluated the safety and efficacy of an innovative everolimus-coated balloon (ECB) in a swine coronary artery model. METHODS: thirty-two swine coronary arteries were prepared through dilatation with a non-coated angioplasty balloon in a closed-chest model. During a period of 90 days, the following four groups (four animals per group, two coronary arteries per animal) were compared for safety and efficacy: A, Rontis ECB with 2.5 µg/mm2 of drug per balloon surface; B, Rontis ECB with 7.5 µg/mm2; C, Rontis Europa Ultra bare balloon; and D, Magic Touch, Concept Medical, sirolimus-coated balloon with a drug load of 1.3 µg/mm2. RESULTS: Differences in local biological effects (arterial reaction scores) and surface of intimal area (mm2) were not statistically significant between the treatment groups. Numerically, group A showed the lowest intimal area and intimal mean thickness, while group B showed the lowest stenosis among all groups. CONCLUSIONS: ECB was safe and effective in a porcine coronary artery model. The dose of everolimus may play a role in the biocompatibility of the balloon.

Evaluation of a new paclitaxel-coated balloon catheter in an in vivo porcine peripheral venous model: Feasibility, safety, and drug deliverability.

PURPOSE: To evaluate in vivo the feasibility, safety, and paclitaxel (PTX) deliverability of a newly developed non-commercially available Paclitaxel-Coated Balloon (PCB) catheter in the swine healthy peripheral vein model. MATERIALS AND METHODS: In total 12 PCBs were deployed in 12 venous segments. Primary feasibility endpoint was the successful application of the devices to the veins of the animals. Primary efficacy endpoint was the determination of the drug content in the venous tissue at 24 h and 7 days after balloon expansion, as assessed by analysis of the vein tissue with High Performance Liquid Chromatography (HPLC) coupled with tandem mass spectrometry. Primary safety endpoint was freedom from any major adverse event. Secondary endpoint was the investigation of any independent factor affecting the primary endpoints. RESULTS: Paclitaxel was detected in five out of six tissue samples 24 h post-intervention and five out of six tissues at 7 days following the procedure (10 tissue samples out of 12). The mean weight of tissue that was examined was 0.20604 ± 0.29822 g (range: 1.02823-0.03377 g) and the mean PTX concentration detected was 8.4 ± 13.1 µg/g (range: 0-36.1 µg/g). The average drug content detected at 24 h (17.1 ± 17.1 µg/g) was numerically superior, but non-statistically significant, compared to 7 days (3.1 ± 3.6 µg/g). An average of 33.8% of the drug remained on the balloon after retrieval. According to the multiple linear regression analysis, there was no significant correlation between transition time, PTX remaining on the balloon, time of analysis (24 h/7 days) and PTX tissue concentration. No abnormalities were noted during autopsy. CONCLUSION: The newly developed PCB successfully delivered within the healthy venous wall a dose of Paclitaxel that inhibits neointimal hyperplasia. No safety issues were raised at short-term follow-up.

Ultrasound-guided femoral approach for coronary angiography and interventions in the porcine model.

Coronary angiography and percutaneous coronary intervention (PCI) procedural details in swine are similar to those performed to humans, since their heart and coronary anatomy closely resembles. However, only a few detailed descriptions of the procedure are available, containing notable differences. We present a feasible and reproducible protocol for percutaneous coronary interventions in porcine experimental models, utilizing ultrasound-guided femoral approach. Nine female pigs were studied to explore the feasibility of superficial femoral arterial (SFA) access for coronary angiography and provisional PCI, as well as the most suitable guiding coronary catheters and angiographic projections for the above interventions. Experiments were performed under general anesthesia, using ultrasound-guided puncture of the SFA to gain arterial access. The Amplatzer AR1® catheter, and the Right Coronary Bypass® catheter were used for the selective engagement of the right and the left coronary artery, respectively. Successful arterial access and subsequent cardiac catheterization were performed in all pigs. Only one animal required a second puncture for femoral artery access. None of the 9 animals presented any significant tachycardia or hypotensive episode. One animal developed an access site-related complication following the first catheterization procedure. During follow-up, 100% success of SFA catheterization was achieved using the same ultrasound-guided technique. The ultrasound-guided superficial femoral artery access for coronary angiography and provisional interventions in porcine models is a quick and safe alternative to the carotid artery approach. The RCB and AR1 catheters may be the best choice for the quick and easy selective coronary engagement of the right and left ostia, respectively.

Histopathological evaluation of a retinoic acid eluting stent in a rabbit iliac artery model.

This study aimed to evaluate the safety and efficacy of innovative retinoic acid (RA) eluting stents with bioabsorbable polymer. Sixty stents divided in ten groups were implanted in the iliac arteries of 30 rabbits. Two polymers ("A", poly (lactic-co-glycolic acid) and "B", polylactic acid), and three doses ("Low", "Medium" and "High") of RA (groups: AL, AM, AH, BL, BM, BH) were used on cobalt chromium stents (Rontis Corporation), one group of bare stent (C), one group (D) of Everolimus eluting stent (Xience-Pro, Abbot Vascular), and two groups of Rontis Everolimus eluting stents coated with polymer A (EA) and B (EB). Treated arteries were explanted after 4 weeks, processed by methyl methacrylate resin and evaluated by histopathology. None of the implanted stents was related with thrombus formation or extensive inflammation. Image analysis showed limited differences between groups regarding area stenosis (BH, D and EB groups had the lower values). Group BH had lower intimal mean thickness than AH (105.1 vs 75.3 µm, p = 0.024). Stents eluting RA, a non-cytotoxic drug, were not related with thrombus formation and had an acceptable degree of stenosis 4 weeks post implantation. RA dose and type of polymer may play role in the biocompatibility of the stents.

Investigation of the drug release time from the biodegrading coating of an everolimus eluting stent.

This case-study examines the release time of the everolimus drug from an experimental biodegrading coating of a Rontis corp. drug eluting stent (DES). The controlled drug release is achieved by the degradation of the coating, which consists of a mixture of polylactic co-glycolic acid (PLGA) and everolimus (55:45). In our analysis, we used the outcome of another study, which contains the geometry of an in-silico deployed Rontis corp. stent in a 3D reconstructed coney arterial segment. Using this geometry as input, the everolimus release was simulated using a computational model that includes: i) modeling of the blood flow dynamics, ii) modeling of PLGA degradation, and iii) modeling of the everolimus advection and diffusion towards both the lumen and the arterial wall. The results show the rapid release of everolimus. This is justified due to the high porosity of the coating, which is caused by the initial high concentration of everolimus in the coating.Clinical Relevance - The methodology presented in this work is an additional step towards predicting accurately drug release from DES. Also, the results of our work prove that high drug concentration in the coating causes its rapid release, which could be used as input in the design of new DES.

Use of Vitamin D Bolus in Fortified Juice for Improving Vitamin D Status in Children with Cerebral Palsy.

Children with cerebral palsy (CP) are at risk of poor nutrition due to a number of factors. Feeding, eating, drinking, and swallowing (FEDS) problems are common in these children and may result in protein-calorie malnutrition usually accompanied by micronutrient deficiencies. Vitamin D is among the elements whose uptake is obstructed. Insufficient exposure to solar radiation in children and adolescents with CP adds to further decreasing serum vitamin D levels thus potentially affecting growth, bone density, and muscle function. Since maintaining long-term adherence to daily oral administration of vitamin D in this population is often difficult, bolus therapy by using vitamin D-fortified products could be an alternative way of effective and safe vitamin D intake. PURPOSE: Assessing the efficacy of administration of bolus vitamin D in fortified juice for increasing 25(OH)D levels in a group of 15 children with CP. RESULTS: The juice was well tolerated, and a significant increase in 25(OH)D levels was observed from 54.1 to 110.3 nmol/L (p < 0.0001) 4 weeks after the administration without any case of hypercalcemia. CONCLUSION: Bolus therapy with vitamin D3-fortified juice is well tolerated and effectively increases 25(OH)D levels in children with CP.

Increased Body Mass Index (BMI) and Sunscreen Use Are Associated with Inadequate Vitamin D Status in Greek Adults in Winter : BMI, Sunscreen Use and Vitamin D Status in Greek Adults.

Vitamin D deficiency is common even in sunny countries like Greece, especially during winter and is associated with skeletal disorders and additionally with increased risk for chronic diseases and adipose metabolic diseases such as obesity and diabetes. The purpose of this pilot study was the determination of vitamin D status in Greek adults and the investigation of possible correlation with lifestyles and somatometric characteristics. The study was conducted during winter and included 36 members (20 women and 16 men) of a university community in central Greece (latitude 39.6° North). Their age was 36.2 ± 16.3 years, body mass index (BMI) 26.4 ± 4.8 (women 26.6 ± 5.6, men 26.3 ± 3.8), and waist circumference 85.7 ± 13.3 cm (women 81.5 ± 13.0, men 90.7 ± 12.4) (mean ± SD). Mean serum 25(OH)D concentration was 20.1 ± 7.3 ng/mL (women 19.7 ± 7.6, men 20.7 ± 7.1). More than half of the participants had 25(OH)D levels below the 20 ng/mL (50 nmol/L) threshold of deficiency. There was a significant negative association between the use of sunscreen during summer and serum 25(OH)D concentrations during winter and a significant positive association between physical exercise and serum 25(OH)D. Levels of 25(OH)D tended to decrease with increasing BMI in persons with a BMI over 25.0. There is a high prevalence of vitamin D insufficiency in Greek adults during winter. Serum 25(OH)D levels in winter are positively associated with exercise and negatively associated with high BMI and the use of sunscreen during summer.

Use of Fortified Bread for Addressing Vitamin D Deficiency.

Vitamin D deficiency due to inadequate sun exposure and/or inadequate intake from food is very common worldwide, consisting a major public health problem. As prolonged exposure to ultraviolet radiation involves risks, food fortification of staple foods emerges as a favorable solution for addressing vitamin D deficiency. Bread is a suitable candidate for fortification as it is consumed often and is the main carbohydrate source in European countries.The purpose of this study was the evaluation of the bioavailability of vitamin D from a fortified Greek-type bread that was developed as a means for addressing vitamin D deficiency, by comparing the absorption curve of vitamin D in fortified bread in relation to that of plain vitamin supplementation. Two groups of clinically healthy volunteers consumed 25,000 international units (IU) of vitamin D3 (cholecalciferol) either in fortified bread (Group A) or in a plain supplement form (Group B). The baseline plasma concentrations of cholecalciferol were 8.1 ± 6.0 ng/mL and 6.8 ± 3.4 ng/mL in Groups A and B, respectively. After 12, 24, and 48 h, the concentrations of cholecalciferol in Group A were 16.7 ± 4.8, 15.3 ± 8.3 and 11.9 ± 6.0 ng/mL, respectively, and in Group B, 15.2 ± 3.3, 11.6 ± 2.4, and 9.6 ± 3.6 ng/mL, respectively. In both groups, the concentrations of cholecalciferol at 12 and 24 h were significantly higher than the baseline concentrations (p < 0.01). There were no statistically significant differences between the concentrations of cholecalciferol between Groups A and B, at each time point.Cholecalciferol is bioavailable from Greek-type fortified bread and bread could be used for addressing vitamin D deficiency.

Focus on the Use of Resveratrol as an Adjuvant in Glioblastoma Therapy.

Glioblastoma (GB) represents the most common and malignant form of glioma cancer. The Gold Standard in Glioblastoma is neurosurgical tumor removal and radiotherapy treatment in concomitant with temozolomide (TMZ). Unfortunately, because of tumor chemo and radio-resistance during this therapy, the patient's outcome remains very poor, with a median overall survival of about 14.6 months. Resveratrol is a natural polyphenol with a stilbene structure with chemopreventive and anticancer properties. In the present review, we evaluated data from preclinical studies conducted with resveratrol as a possible adjuvant during the standard protocol of GB. Resveratrol can reach the brain parenchyma at sub-micromolar concentrations when administrated through conventional routes. In this way, resveratrol reduces cell invasion and increases the efficacy of radiotherapy (radiosensitizer effects) and temozolomide. The molecular mechanism of the adjuvant action of resveratrol may depend upon the reduction of PI3K/AKT/NF-κB axis and downstream targets O-6-methylguanine-DNA methyltransferase (MGMT) and metalloproteinase-2 (MMP-2). It has been reported that redox signaling plays an important role in the regulation of autophagy. Resveratrol administration by External Carotid Artery (ECA) injection or by Lumbar Puncture (LP) can reach micromolar concentrations in tumor mass where it would inhibit tumor growth by STAT-3 dependent mechanisms. Preclinical evidences indicate a positive effect on the use of resveratrol as an adjuvant in anti-GB therapy. Ameliorated formulations of resveratrol with a favorable plasmatic profile for a better brain distribution and timing sequences during radio and chemotherapy could represent a critical aspect for resveratrol use as an adjuvant for a clinical evaluation.

Vitamin D fortification of foods and prospective health outcomes.

Vitamin D is essential for bone health and has significant roles in non-skeletal health and organ function. Dermal synthesis through exposure to ultraviolet B light is the major natural source of vitamin D, while only a small portion of the necessary amount can be acquired by a diet without fortified foods. In recent years, vitamin D deficiency as a result of lifestyles with inadequate sun exposure, has received increased attention due to its association with the increased risk of serious chronic diseases. This review summarizes our current understanding of food fortification strategies with vitamin D and the resulting health impact. Conventional and biotechnological approaches can be used for the production of new and novel vitamin D rich or vitamin D fortified foods. The availability of a wider range of every-day consumed fortified foods as part of a "Daily D" public health policy can contribute to the improvement of vitamin D status and to prevention of vitamin D deficiency.

Hepatocyte autotaxin expression promotes liver fibrosis and cancer.

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth-factor-like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte-specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. CONCLUSION: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369-1383).

Oxidative stress and antioxidant status in patients with autoimmune liver diseases.

OBJECTIVE: To estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression. METHODS: We determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age. RESULTS: Both AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics. DISCUSSION: We provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.

Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells.

Protein tyrosine kinases (PTKs) are enzymes that transfer phosphate groups to tyrosine residues on protein substrates. Phosphorylation of proteins causes changes in their function and/or enzymatic activity resulting in specific biological responses. There are two classes of PTKs: the transmembrane receptor PTKs and the cytoplasmic non-receptor PTKs (NRTKs). NRTKs are involved in transduction of signals originating from extracellular clues, which often interact with transmembrane receptors. Thus, they are important components of signaling pathways which regulate fundamental cellular functions such as cell differentiation, apoptosis, survival, and proliferation. The activity of NRTKs is tightly regulated, and de-regulation and/or overexpression of NRTKs has been implicated in malignant transformation and carcinogenesis. Research on NRTKs has shed light on the mechanisms of a number of cellular processes including those involved in carcinogenesis. Not surprisingly, several tyrosine kinase inhibitors are in use as treatment for a number of malignancies, and more are under investigation. This review deals with the structure, function, and signaling pathways of nine main families of NRTKs in normal and cancer cells.

Vitamin D biology revealed through the study of knockout and transgenic mouse models.

Early studies identifying vitamin D as an antirachitic factor led to studies in vitamin D-deficient models that resulted in a basic understanding of the mechanism of action of vitamin D. Recent studies using genetically modified mice have provided important new insight into the physiological role of vitamin D at target tissues and the functional significance of vitamin D target proteins, as well as the functional significance of proteins involved in the transport and metabolism of vitamin D. Studies using these mice have played an increasingly important role in elucidating the mechanisms involved in the control of calcium homeostasis and have provided evidence for a role of vitamin D in extraskeletal health.

Prevalence of gastric parietal cell antibodies and intrinsic factor antibodies in primary biliary cirrhosis.

BACKGROUND: We investigated the prevalence of antibodies against gastric parietal cells (GPA), intrinsic factor antibodies (IFA) and the presence of pernicious anemia in a large cohort of primary biliary cirrhosis (PBC) patients as similar data is missing. METHODS: 157 PBC patients and 357 controls (73 with autoimmune hepatitis (AIH), 35 primary sclerosing cholangitis (PSC), 45 HBV, 37 HCV, 36 alcoholic liver disease (ALD), 35 non-alcoholic fatty liver disease (NAFLD) and 96 healthy) were investigated for IgG-isotype-specific GPA and IFA by ELISAs and vitamin-B(12) levels by a microparticle enzyme immunoassay. RESULTS: The detection of IgG-GPA was significantly higher in PBC (31.8%) compared to AIH (10.9%; p=0.001), PSC (0%; p=0.000), HCV (13.5%; p=0.01), HBV (13.3%; p=0.006), ALD (8.3%; p=0.004), NAFLD (11.4%; p=0.003) and healthy (10.4%; p=0.001). IgG-IFA were detected in 12% of GPA-positive PBC patients and in none of the other liver diseases or in healthy (p=0.001). This reactivity was significantly associated with lower vitamin-B(12) levels compared to those with an IFA-negative test (p=0.025). CONCLUSIONS: A significant proportion of PBC patients had IgG-GPA and IFA compared to controls. IgG-IFA were detected only in GPA-positive PBC patients and associated with lower vitamin-B(12) levels compared to those with an IFA-negative test.

Serum retinoic acid, retinol and retinyl palmitate levels in patients with lung cancer.

OBJECTIVES: Epidemiological studies have shown an inverse relationship between dietary vitamin A intake and the risk of developing lung cancer. The aim of this study was to investigate the vitamin A status in patients with lung cancer, by determining the serum levels of retinoic acid, retinol and retinyl palmitate. METHODS: In total, 36 patients with lung cancer and 27 controls were assessed. Of the patients 14 had squamous cell carcinoma, 3 adenocarcinoma, 15 non-small cell lung cancer and 4 small cell lung cancer. Serum retinoic acid, retinol and retinyl palmitate levels were determined with HPLC and UV detection, after liquid extraction. RESULTS: Serum retinol levels did not differ between patients (733.5 +/- 326.4 ng/mL) and controls (734.5 +/- 337.1 ng/mL). The retinyl palmitate concentration tended to be lower in patients (14.3 +/- 9.7 ng/mL) than in controls (16.7 +/- 13.7 ng/mL). The serum retinoic acid levels were significantly lower in patients (1.9 +/- 0.6 ng/mL) than in controls (2.5 +/- 1.1 ng/mL, P < 0.05). A positive correlation was observed between the retinol and retinoic acid levels and retinyl palmitate and retinoic acid levels. CONCLUSIONS: The lower levels of retinoic acid in patients with lung cancer suggest there may be a deficiency or impairment in retinol metabolism in these patients. Further studies with larger numbers of patients are needed to evaluate the possible relationship between serum retinoid levels and lung cancer.

Antioxidant capacity in obstructive sleep apnea patients.

OBJECTIVES: Obstructive sleep apnea syndrome (OSA) results in oxygen desaturation and arousal from sleep. Free oxygen radicals are highly reactive molecules, which can be produced by the OSA phenomenon known as hypoxia/reoxygenation. Hypoxic conditions, such as OSA, may also result in transient depletion of cellular reductants, which constitute a main line of antioxidant defense. Both apneas and hypopneas usually end in arousal, where reoxygenation causes the production of reactive oxygen species (free radicals). Living organisms have developed complex antioxidant systems to counteract reactive oxygen species and to reduce their damage. We evaluated the antioxidant capacity in serum from OSA patients and healthy people in order to confirm the hypothesis that there is a relationship between oxidative stress and OSA. MATERIALS AND METHODS: A physician interviewed 25 participants, determining age, smoking habits and symptoms such as excessive daytime sleepiness and snoring. Physical examination and polysomnography were performed during patients' hospitalization. Antioxidant capacity was measured in blood samples by Trolox Equivalent Antioxidant Capacity assay. RESULTS: Seventeen out of 25 subjects had an apnea/hypopnea index (AHI) greater than 10 (OSA group). The measurement of antioxidant capacity did not differ between the OSA patients and our healthy sample (of 25 subjects, seven with an AHI less than 10). Furthermore, patients with severe OSA (AHI >20, N=14) had linearly negative correlation between antioxidant capacity in their blood samples and AHI (R=-0.551, P=0.041). CONCLUSIONS: Reduced antioxidant capacity in serum is an index of excessive oxidative stress. Patients with severe OSA have reduced values of antioxidant capacity.

Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients.

STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSA) is accompanied by oxygen desaturation and arousal from sleep. Free oxygen radicals are highly reactive molecules which could be produced by the OSA phenomenon of hypoxia/reoxygenation: cyclical alterations of arterial oxygen saturation with oxygen desaturation developing in response to apneas followed by resumption of oxygen saturation during hyperventilation. On the basis of these considerations, it was hypothesized that OSA may be linked to increased oxidative stress. MATERIAL AND METHODS: Twenty-six participants gave an interview during which a physician asked them about their age, smoking habits, and symptoms such as excessive daytime sleepiness and snoring. Physical examination and polysomnography were performed during their hospitalization. Reactive oxygen metabolites (ROMs) were measured in blood samples by the diacron reactive oxygen metabolites (D-ROM) test. RESULTS: Twenty-one out of 26 subjects had an apnea/hypopnea index greater than 5 (OSA group). The measurement of free radicals was high in OSA patients. Furthermore, ROMs values in OSA patients were linearly correlated with the apnea/hypopnea index (R = 0.426; p = 0.042). The predictive value of a positive D-ROM test is 81%. CONCLUSIONS: ROMs were elevated in patients with OSA. When OSA was severe, similarly the value of ROMs in blood samples was enhanced, and the probable underlying mechanism for these events is the hypoxia/reoxygenation phenomenon.