Achyrocline Satureioides (LAM) D.C. Would Improve Sleep Quality in Patients with Obstructive Sleep Apnea Syndrome: a Pilot Study Achyroclinesatureioides (LAM) D.C

135 Achyrocline satureioides and sleep quality

ORIGINAL ARTICLE

Achyrocline satureioides (LAM) D.C. would improve sleep quality in patients with Obstructive Sleep Apnea Syndrome: a pilot study Achyroclinesatureioides (LAM) D.C. pode melhorar a qualidade do sono em pacientes com apneia obstrutiva do sono: um estudo piloto

Marisa Pedemonte1, Felicia Rivera2,3, Martín Testa4, Ricardo Velluti5, Federico Dajas3, Erik Nadruz4

ABSTRACT tamento crônica oral (duração de 3 meses) de uma preparação de AS, com alguns parâmetros do sono. Oito pacientes selecionados Achyrocline satureioides (As) (known as Marcela) is a plant belonging que não possuem outras patologias foram diagnosticados com to the family , with a high content of flavonoids, which Asteraceae SAOS pelo padrão polissonografia (PSG) (5 tratados com AS e justifies its antioxidant and anti-inflammatory properties.- Pre 3 com placebo). AS usado com extração contendo 3 mg/ml de vious clinical studies confirm that compounds with these actions flavonóide quercetina, medida por HPLC, e um preparado semAS , have beneficial effects on patients with Obstructive Sleep Apnea usado como placebo.Outra PSG foi realizada no final do estudo. Syndrome (OSAS). This double-blind pilot study investigates the Os resultados mostraram um aumento estatisticamente significa- influence of chronic oral treatment (3 months duration) with tivo do sono REM (fase R, aumento de 125%) e uma tendência a preparation of As on some sleep parameters. Eight patients de aumento na N2 e N3 (estágios de sono de ondas lentas) em pa- selected as do not possess of other pathologies were diagnosed cientes tratados com AS. Os pacientes não tratados apresentaram with OSAS by standard polysomnography (PSG) (5 treated with resultados aleatórios. A Escala de Sonolência de Epworth reduziu As and 3 with placebo). As extract used containing 3 mg/ml of the significativamente, o que significa melhor na qualidade de vida e -es flavonoid quercetin, measured by HPLC, and a prepared without tado de alerta. Não houve mudanças nas taxas de apnéia/hipopnéia As was used as placebo. Another PSG was performed at the end ou oximetria. Melhorana qualidade de sono e vigília, mas não apre- of the study. The results showed a statistically significant increase sentou influência direta sobre os parâmetros da SAOS, pode ser of REM sleep (Stage R, 125% increase) and an increasing trend in justificada pela ação antioxidante e anti-inflamatórias descritas para N2 and N3 stages (slow wave sleep) in patients treated with . As os polifenóis, conteúdos em preparações de AS. Untreated patients showed random results. The Epworth Sleepiness Scale decreased significantly, which means better quality of life Descritores: achyrocline, apneia do sono tipo obstrutiva, and waking. There were no changes in rates of apnea/hypopnea flavonoids. or oximetry. Improving the quality of sleep and wakefulness, but not a direct influence on the parameters of OSAS, could be justi- fied by the antioxidant and anti-inflammatory actions described for INTRODUCTION polyphenols, contents in preparations of As. Obstructive Sleep Apnea Syndrome (OSAS) is a common Keywords: achyrocline, flavonoids, obstructive sleep apnea. disorder (affecting about 4% of middle-aged men and 2% of middle-aged women) where patient exhibits repetitive episodes RESUMO of partial or complete obstruction (apnea) of the upper airway during sleep, producing oxyhemoglobin desaturation, sleep frag- SatureioidesAchyrocline (AS) (conhecido como Marcela) é uma planta pertencente à família das Asteraceae, com um elevado teor mentation, and excessive daytime sleepiness. Increasing evidence de flavonóides, que justifica a sua propriedades antioxidantes e suggests that OSAS is associated with hypertension and other anti-inflamatórios. Estudos clínicos prévios confirmam que os cardiovascular diseases, metabolic derangement, and impaired compostos com estas ações têm efeitos benéficos em pacientes glucose tolerance(1). These episodes of hypoxia/re-oxygenation com Síndrome da Apnéia Obstrutiva do Sono (SAOS). Este é um (2) estudo piloto duplo-cego que objetiva investigar a influência do tra- may induce the generation of oxygen free radicals . In fact,

Study carried out at Facultad de Medicina CLAEH and Instituto de Investigaciones BIológicas Clemente Estable. 2 Cátedra de Fisiología. Facultad de Medicina, Instituto Universitario CLAEH. Punta del Este, Uruguay. 3 Departamento de Neuroquímica. Instituto de Investigaciones Biológicas Clemente Estable. 4 Centro de Medicina del Sueño. Unidad Asociada Facultad de Medicina CLAEH. Punta del Este. Uruguay. 5 Neuro-Otología Experimental y Sueño. ORL., Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay. Corresponding author: Marisa Pedemonte. Cátedra de Fisiología. Facultad de Medicina, Instituto Universitario CLAEH. Prado & Salt Lake, Punta del Este, Uruguay. Phone: (598) 42496612 ext 118. E-mail: [email protected] Financial Support: Partialli financied by Grinlab laboratory. Received: April 10, 2013; Accepted: July 24, 2013.

Sleep Sci. 2013;6(4):135-140 Pedemonte M, Rivera F, Testa M, Velluti R, Dajas F, Nadruz E 136 several studies support that OSAS is associated with oxidative and intraperitoneal way) with marcela was developed. This study stress, and then patients with OSAS have analteration in anti- showed that the Maximum Tolerated Dose of 5 g/kg, did not oxidant defenses. Simiakakis et al.(3) showed that the obesity, show evidence of toxicity in any of the animals organs, neither smoking and sex are the most important determinants of oxida- liver nor kidney toxicity was evidenced(8). tive stress in OSAS subjects. Sleep apnea might enhance oxida- The beneficial effect of As has been ascribed to its tive stress through a reduction of antioxidant capacity of the content in polyphenols and flavonoids that include: caffeic acid, blood due to hypoxia related to respiratory events. 2 esters of calleryain (3,4-dihydroxybenzyl alcohol-4-glucoside), Inflammation is one of the postulated links between galangin, quercetin, quercetin-3-methyl ether(14,16) luteolin, OSAS and increased cardiovascular morbidity. Indeed, the scoparol(14,17) and a new chalcone: achyrobichalcone(18), between pro-inflammatory transcription factor NF-kB is upregulated other compounds. In special the quercetin a molecule that has in OSAS. This is mediated by the alterations between hypoxia been shown to be neuroprotective in several models in vitro(19) and and reoxygenation, along with sleep deprivation.NF-kB plays a in vivo(8,20), and has shown antioxidant(21) and anti-inflammatory(22) key role in inflammatory responses, regulating the expression capacity. Also Luteolin showed antioxidant(23) and anti- of inflammatory genes(4). Recent data demonstrate that OSAS inflammatory(9) effects in experimental models. is characterized by inflammatory response(5). In this sense it is Our aim was to explore the putative benefits of oral possible to assume that compounds with antioxidant and anti- chronic treatment of As preparation in the sleep disorder in inflammatory capacity may provide potential benefits against patients with OSAS. OSAS. Polyphenols are natural compounds with variable phe- nolic structures and are rich in vegetables, fruits, grains, bark, MATERIAL AND METHODS roots, tea, and wine. Most polyphenols have anti-oxidant, anti- Plant material inflammatory, and antiapoptotic properties and their protective The As was obtained from Institute of Agriculture Investigations effects on mitochondrial functioning, glutamate uptake, and (INIA, Uruguay), it was identified by Ing. Agr. P. Davies. A regulating intracellular calcium levels in ischemic injury in vitro voucher specimen of As was kept in the College of Agronomy have been demonstrated(6). Fruits and vegetables, foods rich in Republic University, Montevideo (MVFA32796). flavonoids and antioxidants, have been associated with lower risk of stroke, coronary heart disease, and markers of inflammation Hydro-alcoholic extract of As and oxidative stress in adults(7). Especially flavonoids are a The maceration process of the extract was performed using a valuable source of natural compounds with antioxidant and Soxhlet industrial size, a heater with a capacity of 50 liters of anti-inflammatory actions(8,9). alcohol (ethanol/water to 70%) and a bed for the vegetal product Burckhardt et al.(10) showed to the oral Green Tea Catechin of 50 liters too. This bed is filled with 5kg of dried marcela and Polyphenols (GTP) administration attenuates the intermittent hy- 3 extractions were performed on each bed. The vegetal product poxia (IH) that characterizes sleep disordered. The IHincreases content in the bed is changed 4 to 5-fold to obtain a quercetin NADPH oxidase activity and oxidative stress in rodents. GTPs content of 3 mg/ml, measured by HPLC. The yield obtained by may attenuate IH-induced neurobehavioral deficits by reducing extraction was approximately 1kg of extract per kg of marcela IH-induced NADPH oxidase expression, lipid peroxidation, and (1:1). The placebo was used inert colored liquid, similar to the inflammation. However, the potential therapeutic role of GTP in color of the original extract. Preparations (As and placebo) dif- sleep-disordered breathing deserves further. fer in smell, but patients accessing only one of the preparations The enormous variety of native plants of the South ignoring the other features. The extract and the placebo were American region has been very poorly studied on their value in packed in bottles for up to 25ml previously sterilized. the prevention of nervous system diseases(11). In a large Southern South America region that covers Argentina, Uruguay, Brazil Quercetin quantification in the extract and Paraguay there are numerous plants with a great arsenal of Each lot was tested in the quercetin concentrations according molecules with antioxidant and anti-inflammatory capacity. In to a standard procedure in a Waters modular HPLC system particular Achyrocline satureioides (As) (marcela) belongs to the (Waters Associates, Milford, MA.)(24). Separation of constituents Asteraceae family being a widely distributed South American was achieved by reverse-phase HPLC using a C18 col- native medicinal plant whose decoctions or infusions have umn (Phenomenex, USA) with 5 mm particle size. A binary been traditionally used for gastrointestinal disorders, as an HPLC pump (Waters 1525) with a 717 plus autosampler Wa- emmenagogue and menstrual regulator and as a sedative and ters and a photodiode array detector Waters 2998 linked to antispasmodic(12). The antioxidant capacity and free radical scav- Empower 2 (Waters) chromatography data software was uti- enging of As has been demonstrated in diverse experimental lized. The temperature of the column was set at 30 °C. The models and it was reported that As protected cells in culture mobile phase used was: (A) 100% MeOH, (B) 0.5% H3PO4 against an oxidative insult(13-15). As is a plant widely consumed pH = 2,5% MeOH, at 0.7 ml/min. The gradient system con- by South America population, during many years andno cases sisted of (min/%B): 0/80, 40/0, 41/80, 47/80. The eluant was of toxicity have been reported. However a sub-chronic toxicity monitored by photodiode array detection at 375 nm and spectra study in mice and rats and in two administration routes (oral of products obtained between 210-600 nm.

Sleep Sci. 2013;6(4):134-140 137 Achyrocline satureioides and sleep quality

Patients extract dosage electromyograms, eye movements, oxygen saturation and respi- The preparation has a Total Polyphenolcontentof 14.8EAC ration (nasobuccal flow, abdominal and thoracic movements). (Equivalentof caffeic acid) mg/ml and a quercetin concentration of3 mg/ml. When patients ingested 25 drops (approximately 2ml) Data processing of the preparation, will be incorporated EAC 30mg/ml and Each patient was analyzed as its own control. The off-line sleep 6mg/ml of quercetin. Twice a day represent 60EAC mg/ml of recording analysis was performed manually by a trained judge. total polyphenols and 12 mg/ml of quercetin. The quercetin dose The changes were statistically analized by the Mann Whitney´s given by us in this study have been suggested in several studies Test, using a 95% confidence intervals. performed in athletes undergoing intense exercise and where a The terminology recommended by the Manual for preparation rich in polyphenols have shown decrease oxidative scoring sleep (2007) of the American Academy of Sleep stress caused by the effort(25,26). Preparation that was used as a Medicine were used: Stages N1, N2, N3 and R, correspond- placebo had similar color and appearance that the extract stud- ing to classical Stages 1-2, 3-4 slow wave sleep, and Paradoxical ied but did not contain As. The placebos experimental subjects Sleep or REM (Rapid Eye Movements) respectively(27). were randomized and without knowledge of their status in the All participants signed their consent after being fully study, although this possibility was previously informed. informed of the goal and characteristics of the study. This research was approved by the Medical School Ethical Committee Experimental protocol for Human Research of the CLAEH Faculty of Medicine, Patients recruitment accordance with international guidelines for human research. Forty one volunteers were interviewed, 23 did not meet the clinical inclusion criteria. Five out of the remaining 18 RESULTS did not suffer OSAS underwent polysomnography (PSG). Changes in sleep parameters were found in patients treated Thirteen patients started the study and 5 of them dropped- with As, the most evident was the increment in the Stage R or out (because abandoned or not properly complied with the REM (125% of increment in the averaged 5 patients, statistically established protocol), leaving 8 patients fulfilling the 3 months significant) comparing the first PSG (control) with the last one, of treatment. This pilot study has been conducted with a after As treatment (Figure 1). Stages N2 and N3 also shifted, double-blind protocol; patients selected a random number showing a tendency to increase (Table 1). These increases occur corresponding to As extract or placebo, were unaware of at the expense of a decrement of the awakening periods that which group belonged (5 patients were treated with As and occur during the night as well as the decrease in light sleep, 3 with placebo). Three out of 5 of the treated group were stage 1 (N1). The Apnea/Hypopnea Index (AHI) increased in women (Table 1), all of them were postmenopausic and with- 3 of the 5 patients treated with As, decreasing in the remaining out hormonal replacement. Two out of the placebo´s group 2. Oximetry showed no improvement in the mean values or were women, one of them postmenopausic and the other one minimum values, the average values dropped in 3 patients and (26 years old). Only one person of the clinical staff knew the kept in two, while the minimum values lowered in 2 and rose in patients´ group, those that performed the PSG, the scoring 3 following administration of As. of sleep stages and statistical analyzes did not know in which The subjective perception of sleep quality also improved group were the patients. not only for the patient but for the room partner (less movement, Inclusion criteria were: (1) OSAS diagnosis without less snoring, less awakes). These changes were accompanied previous treatment and non-smoking status; (2) patients by the subjective perception of better quality of life (decrease should not take any medication or suffer any additional disease in headaches, more alert, improved memory, and better job (hypertension and obesity were the only ones tolerated). The age performance), and the objective decrement in the ESS (Figure 2 range was between 26 and 62 years old. and Table 1). Some patients refer increment in the sleep time, it At the beginning each patient was evaluated with the PSG was not demonstrated statistically. The sleep time average was and the sleepiness at daytime with the Epworth Sleepiness Scale about 8 hours, since 11:00 pm to 7:00 am. (ESS). The PSG and ESS were repeated at the end of the protocol The placebo group showed random results in poli- (3 months later). At the end also were applied a questionnaire (20 somnographic parameters. Patients do not report improvement questions) that explored the subjective perception of sleep quality in either the ESS or the subjective perception of sleep. However, (from the own patient perception and from the room partner) no changes either in the oximetry or in Apnea Hipopnea Index and changes in the subjective perception of the quality of life. appeared; no differences between As treated and placebo´s Patients were asked if each situation presented had improved, group were found (Table 1). worsened or remained unchanged. DISCUSSION Polysomnographic recording Based on the results showed in this pilot study we can speculate The PSG was carried out as any regular PSG clinical test. A that the improvements in sleep quality could be related to the Polysomnograph (Akonic SA, Argentina) was used recording polyphenolic actions present in the As preparation; nevertheless, six electroencephalographic channels, electrocardiogram, these changes are not clearly dependent on improvement in OSAS.

Sleep Sci. 2013;6(4):135-140 Pedemonte M, Rivera F, Testa M, Velluti R, Dajas F, Nadruz E 138

Table 1. Patients treated with Achyrocline satureioides (As). Sleep Stages (% of total recording time) Patients AHI Oximetry Oximetry ESS Stage N2 Stage N3 Stage R #, sex, age, Control Post As Control Post As Control Post As Control Post As Control Post As Control Post As Control Post As BMI (average) (average) (M.V) (M.V.) 1, M, 34, 27 52 32 96 93 86 87 12 8 25 20 58 49 3 14 3, F, 58, 43 5 12 96 96 79 76 20 8 31 18 51 55 6 10 10, F, 52, 27 78 84 93 88 71 67 20 12 11 33 11 50 1 10 11, F, 50, 33 24 31 95 94 78 76 13 9 30 41 32 31 6 6 18, M, 40, 10 4 96 96 76 81 17 7 32 35 48 40 3 7 35 Average 34 33 95 93 78 77 16 9 26 29 40 45 4 9 Statistical p < 0.05 p < 0.05 analysis Patients treated with Placebo (Pl). Sleep Stages (% of total recording time) Patients AHI Oximetry Oximetry ESS Stage N2 Stage N3 Stage R #, sex, age, Control Post As Control Post As Control Post Pl Control Post Pl Control Post Pl Control Post Pl Control Post Pl BMI (average) (average) (M.V) (M.V.) 9, M,47,37 31 35 94 94 70 71 16 18 19 17 65 51 11 26 13,F,62,32 7 8 96 96 86 91 23 21 22 25 42 16 2 3 16,F,26,30 6 7 97 98 86 89 16 13 12 42 70 28 16 12 Average 15 17 81 84 81 84 18 17 18 28 59 32 10 14 AHI: Apnea-hypopnea index (events per hour of sleep); BMI: Body mass index; ESS: Epworth sleepiness scale; Oximetry: M.V. Minimun value; Stage N2: Sleep with spindles and K complex; Stage N3: Slow wave sleep stages III and IV; Stage R: Paradoxical sleep or REM (Rapid Eye Movements).

Figure 1. Effect of Achyrocline satureioides (As) in five patients suffering Obstruc- tive Sleep Apnea Syndrome is shown (mean and standard deviation). Percentages of Stages N2, N3 en R (or REM) were compared previous (control, C) and after the As treatment (As). The three stages showed increment being statistically significant in Stage R (p < 0.05, Mann-Whitney´s test, 95% confidence intervals). Figure 2. Epworth Sleepiness Scale before (Control) and after treatment with Achyrocline satureioides (Post As) is shown (mean and standard deviation). Changes are statistically significant p( < 0.05, Mann-Whitney´s test, 95% confidence intervals). OSAS is a medical disorder strongly associated with multiple co-morbidities. Current evidence suggests that OSAS disturbs funda- OSAS. The use of plant-derived supplements for health benefits, mental biochemical processes, leading to low-grade systemic inflam- is gaining popularity because most people consider safe and mation and oxidative stress. Animal models have shown that OSA natural products can produceless side effects than synthetic drugs. may lead to apoptosis of central neurons. In clinical studies, oxygen Research on the health benefits provided by the natural products, desaturation index and sleep fragmentation have been shown to be is considered a major challenge for modern medicine(29). independently associated with cognitive dysfunction(28). As such we decided to explore the benefits of As in the It is for this reason that the polyphenolic compounds, OSAS. The effects antioxidant and anti-inflammatory ofAs has especially flavonoids for their antioxidant and anti-inflammatory been ascribed to its content in polyphenols and flavonoids as: may be a natural alternative to explore against the pathologies caffeic acid, galangin, quercetin, quercetin-3-methyl ether(14,16) associated with inflammation and oxidative imbalance as the luteolin, scoparol(14,17) between other compounds.

Sleep Sci. 2013;6(4):134-140 139 Achyrocline satureioides and sleep quality

The Polyphenol content (14.8EAC) (Equivalent of Acknowledgement caffeic acid) mg/ml and the quercetin concentration (3 mg/ml) The authors thank to Chemical Engineer Jorge Ferrari by del hidro-alcoholic extract of As was quantified with the purpose Grinlab laboratory for economic support. The authors declare of the administration dose of the preparation. In this sense it is no financial/commercial conflict of interest. interesting to note that to produce their beneficial effects, other than on the gastrointestinal (GI) tract itself, the polyphenols REFERENCES must be absorbed into the body after oral ingestion and be 1. McNicholas WT, Bonsigore MR.; Management Committee of EU COST ACTION B26. Sleep apnoea as an independent risk factor for cardiovas- carried by the blood stream from the absorption site to target cular disease: current evidence, basic mechanisms and research priorities. tissues and organs. Biological activity has been demonstrated for Eur Respir J. 2007;29(1):156-78. 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