pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2014-0-3-86-98pulmo-399Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESРАНДОМИЗИРОВАННОЕ ДВОЙНОЕ СЛЕПОЕ ПЛАЦЕБО-КОНТРОЛИРУЕМОЕ ИССЛЕДОВАНИЕ PANTHEON: ПРИМЕНЕНИЕ N-АЦЕТИЛЦИСТЕИНА В ДОЗЕ 600 МГ 2 РАЗА В ДЕНЬ ПРИ ОБОСТРЕНИЯХ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХTWICE DAILY N-ACETYLCYSTEINE 600 MG FOR EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (PANTHEON): A RANDOMISED, DOUBLE-BLIND PLACEBO-CONTROLLED TRIALЖенгДж.-П.ZhengJin-PingВенФ.-К.WenFu-QiangБейЧ.-К.BaiChun-XueВанХ.-Я.WanHuan-YingКангДж.KangJianЧенП.ChenPingЯаоВ.-Ж.YaoWan-ZhenМаЛ.-Дж.MaLi-junЛиК.LiXiaРайтериД.RaiteriLucaСардинаМ.SardinaMarcoГаоИ.GaoYiВангБ.-С.WangBai-SongЗонгН.-Ш.ZhongNan-ShanState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University; Guangzhou, ChinaКитайState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University; Guangzhou, ChinaChinaWest China Hospital, Sichuan University; Chengdu, ChinaКитайWest China Hospital, Sichuan University; Chengdu, ChinaChinaZhongshan Hospital, Fudan University; Shanghai, ChinaКитайZhongshan Hospital, Fudan University; Shanghai, ChinaChinaRui Jin Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai, ChinaКитайRui Jin Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai, ChinaChinaFirst Affiliated Hospital of China Medical University; Shenyang, ChinaКитайFirst Affiliated Hospital of China Medical University; Shenyang, ChinaChinaShenyang PLA General Hospital; Shenyang, ChinaКитайShenyang PLA General Hospital; Shenyang, ChinaChinaPeking University Third Hospital; Beijing, ChinaКитайPeking University Third Hospital; Beijing, ChinaChinaHenan Provincial People's Hospital; Zhengzhou, ChinaКитайHenan Provincial People's Hospital; Zhengzhou, ChinaChinaHainan Zambon Pharmaceutical; Beijing, ChinaКитайHainan Zambon Pharmaceutical; Beijing, ChinaChinaInnovation & Medical Sciences Department, Zambon, Bresso; Milan, ItalyИталияInnovation & Medical Sciences Department, Zambon, Bresso; Milan, ItalyItalyState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University; Guangzhou, ChinaКитайState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, University; Guangzhou, ChinaChinaMedKey Med-Tec Development; Shanghai, ChinaКитайMedKey Med-Tec Development; Shanghai, ChinaChina201428062014038698Copyright © Женг Д., Вен Ф., Бей Ч., Ван Х., Канг Д., Чен П., Яао В., Ма Л., Ли К., Райтери Д., Сардина М., Гао И., Ванг Б., Зонг Н., 20142014Женг Д., Вен Ф., Бей Ч., Ван Х., Канг Д., Чен П., Яао В., Ма Л., Ли К., Райтери Д., Сардина М., Гао И., Ванг Б., Зонг Н.Zheng J., Wen F., Bai C., Wan H., Kang J., Chen P., Yao W., Ma L., Li X., Raiteri L., Sardina M., Gao Y., Wang B., Zhong N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/399

Усиление воспалительных и окислительных процессов играет важную роль в патогенезе хронической обструктивной болезни легких (ХОБЛ). При этом заболевании может быть эффективно применение лекарств с противовоспалительной и антиоксидантной актив- ностью – таких как N-ацетилцистеин (NAC). Целью данного исследования явилась оценка возможности терапии с помощью NAC и снижение частоты обострений ХОБЛ.

В данном проспективном рандомизированном двойном слепом плацебо-контролируемом исследовании в параллельных группах принимали участие пациенты в возрасте 40–80 лет со среднетяжелой и тяжелой ХОБЛ (постбронходилатационное соотношение объема форсированного выдоха за 1-ю секунду – ОФВ1 и форсированной жизненной емкости легких < 0,7 и ОФВ1 – 30–70%долж.) из 34 клиник Китая. Больные были разделены на группы в зависимости от регулярного использования ингаляционных глюкокортикостероидов к началу исследования. В рандомизированном порядке в течение 1 года у пациентов проводилась терапия NAC по 1 таблетке (600 мг) 2 раза в день либо плацебо аналогичного вида. Основным конечным показателем была среднегодовая частота обострений у больных, получивших хотя бы 1 дозу изучаемых препаратов и посетивших клинику хотя бы 1 раз после рандомизации. Исследование зарегистрировано в Национальном регистре клинических исследований Китая, ChiCTR-TRC-09000460.

С 25 июня 2009 по 29 декабря 2010 г. проведен скрининг у больных (n = 1 297), из которых 1 006 соответствовали критериям включения и были рандомизированы в группы NAC (n = 504) и плацебо (n = 502). За 1 год зарегистрировано 497 обострений у 482 больных, получивших хотя бы 1 дозу NAC и хотя бы 1 раз посетивших клинику после рандомизации (1,16 обострения на 1 больного в год), и 641 обострение у 482 больных группы плацебо (1,49 обострения на 1 больного в год; отношение рисков – 0,78; 95%-ный доверительный интервал 0,67–0,90; р = 0,011). NAC хорошо переносился: побочные эффекты зарегистрированы у 146 (29 %) из 495 пациентов, получивших хотя бы 1 дозу препарата, из них 48 были отмечены как серьезные, по сравнению с 130 (26 %) из 495 больных, получавших хотя бы 1 дозу плацебо, из них 46 – серьезных. Наиболее частым серьезным побочным эффектом было обострение ХОБЛ, которое развилось у 32 (6%) из 495 пациентов группы NAC и у 36 (7%) из 495 – группы плацебо.

Полученные результаты свидетельствуют, что у китайских больных среднетяжелой и тяжелой ХОБЛ при длительном применении NAC в дозе 600 мг 2 раза в день возможно предотвращение обострения, особенно при среднетяжелом течении заболевания. Необходимы дальнейшие исследования для изучения эффективности такого лечения у больных с легким течением ХОБЛ (I стадия по GOLD).

Background

Background. Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD.

Methods

Methods. In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40–80 years with moderateto-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) / forcedvital capacity < 0.7 and FEV1 of 30–70 % of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.

Findings

Findings. Between June 25, 2009, and Dec 29, 2010, we screened 1 297 patients, of whom 1 006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1.16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1.49 exacerbations per patient-year; risk ratio 0.78, 95% CI 0.67–0.90; p = 0.0011). N-acetylcysteine was well tolerated: 146 (29 %) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26 %) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6 %) of 495 patients in the N-acetylcysteine group and 36 (7 %) of 495 patients in the placebo group.

Interpretation

Interpretation. Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I).

хроническая обструктивная болезнь легкихобострениеантиоксидантыN-ацетилцистеинвысокие дозыchronic obstructive pulmonary diseaseacute exacerbationantioxidant therapyN-acetylcysteinehigh doseHainan Zambon PharmaceuticalReferencesVestbo J., Hurd S.S., Agusti A.G. et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 2013; 187: 347–365.Vestbo J., Hurd S.S., Agusti A.G. et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 2013; 187: 347–365.Donaldson G.C., Seemungal T.A., Bhowmik A., Wedzicha J.A. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002; 57: 847–852.Donaldson G.C., Seemungal T.A., Bhowmik A., Wedzicha J.A. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002; 57: 847–852.Spencer S., Calverley P.M., Burge P.S., Jones P.W. Impact of preventing exacerbations on deterioration of health status in COPD. Eur. Respir. J. 2004; 23: 698–702.Spencer S., Calverley P.M., Burge P.S., Jones P.W. Impact of preventing exacerbations on deterioration of health status in COPD. Eur. Respir. J. 2004; 23: 698–702.Wouters E.F. The burden of COPD in The Netherlands: results from the confronting COPD survey. Respir. Med. 2003; 97 (Suppl. C): S51–59.Wouters E.F. The burden of COPD in The Netherlands: results from the confronting COPD survey. Respir. Med. 2003; 97 (Suppl. C): S51–59.Blackwell T.S., Blackwell T.R., Holden E.P. et al. In vivo antioxidant treatment suppresses nuclear factor–kappa B activation and neutrophilic lung infl ammation. J. Immunol. 1996; 157: 1630–1637.Blackwell T.S., Blackwell T.R., Holden E.P. et al. In vivo antioxidant treatment suppresses nuclear factor–kappa B activation and neutrophilic lung infl ammation. J. Immunol. 1996; 157: 1630–1637.van Overveld F.J., Demkow U., Gorecka D. et al. New developments in the treatment of COPD: comparing the effects of inhaled corticosteroids and N-acetylcysteine. J. Physiol. Pharmacol. 2005; 56 (Suppl. 4): 135–142.van Overveld F.J., Demkow U., Gorecka D. et al. New developments in the treatment of COPD: comparing the effects of inhaled corticosteroids and N-acetylcysteine. J. Physiol. Pharmacol. 2005; 56 (Suppl. 4): 135–142.Dekhuijzen P.N.R. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur. Respir. J. 2004; 23: 629–636.Dekhuijzen P.N.R. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur. Respir. J. 2004; 23: 629–636.Ueno T., Yamada M., Igarashi Y., Ogawa T. N-acetyl cysteine protects osteoblastic function from oxidative stress. J. Biomed. Mater. Res. A. 2011; 99: 523–531.Ueno T., Yamada M., Igarashi Y., Ogawa T. N-acetyl cysteine protects osteoblastic function from oxidative stress. J. Biomed. Mater. Res. A. 2011; 99: 523–531.Sadowska A.M., Manuel-Y-Keenoy B., De Backer W.A. Antioxidant and anti-infl ammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo doseeffects: a review. Pulm. Pharmacol. Ther. 2007; 20: 9–22.Sadowska A.M., Manuel-Y-Keenoy B., De Backer W.A. Antioxidant and anti-infl ammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo doseeffects: a review. Pulm. Pharmacol. Ther. 2007; 20: 9–22.Grandjean E.M., Berthet P., Ruffmann R., Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebocontrolled clinical trials. Clin. Ther. 2000; 22: 209–221.Grandjean E.M., Berthet P., Ruffmann R., Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebocontrolled clinical trials. Clin. Ther. 2000; 22: 209–221.Gerrits C.M., Herings R.M., Leufkens H.G., Lammers J.W. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 21: 795–798.Gerrits C.M., Herings R.M., Leufkens H.G., Lammers J.W. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 21: 795–798.Decramer M., Rutten-van Molken M., Dekhuijzen P.N. et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomised on N-acetylcysteine Cost-Utility Study, BRONCUS): a randomized placebo-controlled trial. Lancet. 2005; 365: 1552–1560.Decramer M., Rutten-van Molken M., Dekhuijzen P.N. et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomised on N-acetylcysteine Cost-Utility Study, BRONCUS): a randomized placebo-controlled trial. Lancet. 2005; 365: 1552–1560.Schermer T., Chavannes N., Dekhuijzen R. et al. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir. Med. 2009; 103: 542–551.Schermer T., Chavannes N., Dekhuijzen R. et al. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir. Med. 2009; 103: 542–551.Zuin R., Palamidese A., Negrin R. et al. High dose N-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin. Drug Investig. 2005; 25: 401–408.Zuin R., Palamidese A., Negrin R. et al. High dose N-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin. Drug Investig. 2005; 25: 401–408.Zheng J.P., Wen F.Q., Bai C.X. et al. High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON study. COPD. 2013; 10: 164–171.Zheng J.P., Wen F.Q., Bai C.X. et al. High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON study. COPD. 2013; 10: 164–171.Anthonisen N.R., Manfreda J., Warren C.P.W. et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med. 1987; 106: 196–204.Anthonisen N.R., Manfreda J., Warren C.P.W. et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med. 1987; 106: 196–204.Burge S., Wedzicha J.A. COPD exacerbations: defi nitions and classifi cations. Eur. Respir. J. 2003; 21 (Suppl. 41): 46–53.Burge S., Wedzicha J.A. COPD exacerbations: defi nitions and classifi cations. Eur. Respir. J. 2003; 21 (Suppl. 41): 46–53.Zheng J.P., Kang J., Huang S.G. et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008; 371: 2013–2018.Zheng J.P., Kang J., Huang S.G. et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008; 371: 2013–2018.Calverley P.M., Anderson J.A., Celli B. et al. TORCH investigators. Salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 2007; 356: 775–789.Calverley P.M., Anderson J.A., Celli B. et al. TORCH investigators. Salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 2007; 356: 775–789.Tashkin D.P., Celli B., Senn S. et al, for the UPLIFT study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. 2008; 359: 1543–1554. 21. Zhou Y., Wang X., Zeng X. et al. Positive benefi ts of theophylline in a randomised, double-blind, parallel-group, placebo controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006; 11: 603–610.Tashkin D.P., Celli B., Senn S. et al, for the UPLIFT study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. 2008; 359: 1543–1554. 21. Zhou Y., Wang X., Zeng X. et al. Positive benefi ts of theophylline in a randomised, double-blind, parallel-group, placebo controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006; 11: 603–610.Tse H.N., Raiteri L., Wong K.Y. et al. High-dose N-acetylcysteine in stable chronic obstructive pulmonary disease: the 1-year, doubleblind, randomised, placebo-controlled HIACE study. Chest. 2013; 144: 106–118.Tse H.N., Raiteri L., Wong K.Y. et al. High-dose N-acetylcysteine in stable chronic obstructive pulmonary disease: the 1-year, doubleblind, randomised, placebo-controlled HIACE study. Chest. 2013; 144: 106–118.Jenkins C.R., Jones P.W., Calverley P.M. et al. Efficacy of salmeterol / fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir. Res. 2009; 10: 59.Jenkins C.R., Jones P.W., Calverley P.M. et al. Efficacy of salmeterol / fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir. Res. 2009; 10: 59.Decramer M., Celli B., Kesten S. et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecifi ed subgroup analysis of a randomized controlled trial. Lancet. 2009; 374: 1171–1178.Decramer M., Celli B., Kesten S. et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecifi ed subgroup analysis of a randomized controlled trial. Lancet. 2009; 374: 1171–1178.Zheng J.P., Zhong N.S., Jiang M., Zeng G.Q. Carbocisteine for acute exacerbations of COPD-authors' reply. Lancet. 2008; 372: 1631–1632.Zheng J.P., Zhong N.S., Jiang M., Zeng G.Q. Carbocisteine for acute exacerbations of COPD-authors' reply. Lancet. 2008; 372: 1631–1632.Hurst J.R., Vestbo J., Anzueto A. et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N. Engl. J. Med. 2010; 363: 1128–1138.Hurst J.R., Vestbo J., Anzueto A. et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N. Engl. J. Med. 2010; 363: 1128–1138.Zheng J.P., Yang L., Wu Y.M. et al. The efficacy and safety of combination salmeterol (50 μg)/fl uticasone propionate (500 μg) inhalation twice daily via Accuhaler in Chinese patients with COPD. Chest. 2007; 132: 1756–1763.Zheng J.P., Yang L., Wu Y.M. et al. The efficacy and safety of combination salmeterol (50 μg)/fl uticasone propionate (500 μg) inhalation twice daily via Accuhaler in Chinese patients with COPD. Chest. 2007; 132: 1756–1763.Zhong N., Wang C., Yao W. et al. Prevalence of chronic obstructive pulmonary disease in China: a large populationbased survey. Am. J. Respir. Crit. Care Med. 2007; 176: 753–760.Zhong N., Wang C., Yao W. et al. Prevalence of chronic obstructive pulmonary disease in China: a large populationbased survey. Am. J. Respir. Crit. Care Med. 2007; 176: 753–760.Calverley P., Pauwels R., Vestbo J. et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003; 361: 449–456.Calverley P., Pauwels R., Vestbo J. et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003; 361: 449–456.Thomsen M., Nordestgaard B.G., Vestbo J. et al. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir. Med. 2013; 1: 543–550.Thomsen M., Nordestgaard B.G., Vestbo J. et al. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir. Med. 2013; 1: 543–550.Zhong N., Zheng J., Wen F. et al. Efficacy and safety of budesonide / formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease. Curr. Med. Res. Opin. 2012; 28: 257–265.Zhong N., Zheng J., Wen F. et al. Efficacy and safety of budesonide / formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease. Curr. Med. Res. Opin. 2012; 28: 257–265.Stav D., Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomised placebo-controlled study. Chest. 2009; 136: 381–386.Stav D., Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomised placebo-controlled study. Chest. 2009; 136: 381–386.Mata M., Sarrion I., Armengot M. et al. Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine. PLoS One. 2012; 7: e48037.Mata M., Sarrion I., Armengot M. et al. Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine. PLoS One. 2012; 7: e48037.

The authors declare that there are no conflicts of interest present.