Journal of Ethnopharmacology 196 (2017) 186–192 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep Squill Oxymel, a traditional formulation from Drimia Maritima (L.) Stearn, MARK as an add-on treatment in patients with moderate to severe persistent asthma: A pilot, triple-blind, randomized clinical trial ⁎ Fatemeh Nejatbakhsha, Hossein Karegar-Borzia, , Gholamreza Aminb, Alireza Eslaminejadc, ⁎ Mostafa Hosseinid, Mahbubeh Bozorgie, Mehrnaz Asadi Gharabaghif, a Department of Iranian Traditional Medicine, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran b Department of Pharmacognosy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran c Department of Pulmonary Medicine, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran d Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran e Department of Traditional Pharmacy, Faculty of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran f Department of Pulmonary Medicine, Imam Khomeini Hospital, Keshavarz Boulevard, Medical Sciences/Tehran University, Tehran, Iran ARTICLE INFO ABSTRACT Keywords: Ethnopharmacological relevance: In Traditional Iranian Medicine (TIM), Squill (Drimia maritima (L.) Asthma Stearn) Oxymel was utilized in the treatment of asthma. Squill has been reported to exert anti-inflammatory, Drimia maritima (L.) Stearn anti-oxidant, anti-cholinergic, and mucus secretion modulating effects. Squill Oxymel Objective: This study aimed to make a preliminary evaluation of the efficacy and safety of an add-on Squill Traditional medicine Oxymel treatment in patients with moderate to severe persistent asthma. Airway resistance Methods: In a 6-week, triple-blind, randomized, placebo-controlled trial, 60 patients with stable moderate to severe persistent asthma were randomly allocated to receive either 10 ml syrup of Squill Oxymel, simple oxymel, or a placebo 2 times a day, as an add-on to their routine treatment (inhaled corticosteroids and β2 agonists). Spirometry and plethysmography were performed on patients to evaluate the effect of the treatment at baseline and end of intervention. Forced Expiratory Volume in first second (FEV1) was considered the primary outcome. St. George's respiratory questionnaire (SGRQ) was also used for the subjective evaluation of patients' responses. Results: Fifty-four patients completed the study. The results showed significant improvement in spirometry parameters, especially FEV1 (1.54 ± .38 vs. 2.11 ± .49 l), in the Squill Oxymel group compared with the other groups. The increases in FEV1 liter, FEV1%, FEV1/FVC%, and MEF 25–75% during the intervention were significantly higher in the Squill Oxymel group than in the other groups (p < .001). However, the improvement of plethysmographic parameters showed no significant difference between the study groups (p>.05). The SGRQ scores (symptoms, activity, and total score) were significantly improved after intervention in both the Squill Oxymel and the simple honey oxymel groups (p < .001), but not in the placebo group. Nausea and vomiting was reported in 5 patients in Squill oxymel and simple oxymel groups. No other serious adverse event was observed. Conclusions: The results of the current study show preliminary evidence for the efficacy and safety of the add- on treatment of Squill Oxymel in patients with moderate to severe persistent asthma. 1. Introduction expected that the number of asthmatic patients in the world will increase by another 100 million by 2025 (Masoli et al., 2004). In the Asthma is among the most common chronic diseases worldwide. It United States alone, the annual cost of asthma is estimated at 56 billion affects about 300 million people (Longo et al., 2012) resulting in dollars (Barnett and Nurmagambetov, 2011). approximately 250,000 deaths annually (Bousquet et al., 2010). It is A cascade of inflammatory mediators plays a central role in the Abbreviations: TIM, Traditional Iranian medicine; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; MEF25-75%, forced expiratory flow between 25% and 75%; PEF, peak expiratory flow; TLC, total lung capacity; RV, residual volume; RAW (ex, in), airway resistance (inspiratory, expiratory); TGV, thoracic gas volume; IC, inspiratory capacity; sRaw, specific airway resistance ⁎ Corresponding authors. E-mail address: [email protected] (M.A. Gharabaghi). http://dx.doi.org/10.1016/j.jep.2016.12.032 Received 6 August 2016; Received in revised form 12 December 2016; Accepted 16 December 2016 Available online 18 December 2016 0378-8741/ © 2016 Elsevier Ireland Ltd. All rights reserved. F. Nejatbakhsh et al. Journal of Ethnopharmacology 196 (2017) 186–192 pathophysiology of asthma. Currently, inhaled corticosteroids (ICS) are persistent asthma. The study protocol was reviewed and approved by the mainstay of asthma treatment. Despite their positive effect on the Research Ethics Committee of Tehran University of Medical asthma control, evidence shows their incomplete efficacy in asthmatic Sciences (ethical code: 126326) and conducted in accordance with patients (Nomellini and Chen, 2012). ICS are not completely safe, and the Declaration of Helsinki (Association, 2009). The study was fully reports of their various side effects are increasing. Complications such supported financially by the Research Department of Tehran University as posterior sub-capsular and nuclear cataracts (Cumming et al., 1997), of Medical Sciences (Grant No. 9021309004) and registered in IRCT ocular hypertension or open-angle glaucoma (Garbe et al., 1997), bone (ID: IRCT2014111119912N1). All patients provided written informed loss (Richy et al., 2003), and mild adrenal and growth suppression in consent before participating in the study. children have been reported for ICS (Kannisto et al., 2000). Therefore, it is reasonable to look for controlling drugs with low adverse effect 2.2. Sample size calculation capable of reducing the dosage of administered steroid. Practitioners of traditional Iranian medicine (TIM) such as Rhazes Pre-calculated tables for analysis of variance were used to deter- (d. 925 CE) (Heydari et al., 2015), Haly Abbas (d. 982 CE) (Heydari mine sample size (Neter et al., 1996). Based on previous studies and et al., 2014), and Avicenna (d. 1037 CE) (Mosavat et al., 2015) used the mentioned tables, a sample size of 17 patients per group was multiple herbal formulations to treat asthma (Amirghofran, 2010; calculated for at least 10% improvement in forced expiratory volume in Boskabady et al., 2010; Qasemzadeh et al., 2015). Squill, in the first second (FEV1). After adding a possible dropout rate of 20%, the formulation of Squill Oxymel, was the most commonly used drug in sample size of 20 participants in each group was selected. the treatment of asthma (Aghili, 2009; Ibn Sina, 2005). 2.3. Patients 1.1. Squill: (Drimia maritima (L.) Stearn) Patients with moderate to severe persistent asthma with asthma Drimia maritima (L.) Stearn (Squill) is native to the Mediterranean control test (ACT) score less than 20 who referred to the outpatient region, Africa, and India (Stedje, 1987) (12). This plant and its pulmonary clinic of Imam Khomeini hospital, affiliated with Tehran formulations like Squill Oxymel were widely used by TIM practitioners University of Medical Sciences, Tehran, Iran, were recruited for this to treat different disorders (Aghili, 2009; Ibn Sina, 2005), including study between January and July 2015. melancholia, paralysis, dyspepsia, flatulence, jaundice, ascites, sciatica, The diagnosis criteria for moderate to severe persistent asthma and arthritis. However, Squill Oxymel was most popularly used for were based on the Global Initiative for Asthma (GINA) guidelines respiratory disorders such as hoarseness, pneumonia, chronic bron- (Bateman et al., 2008) (25). All patients were being actively treated chitis, chroniccough, and asthma (Aghili, 2009; Ibn Sina, 2005; with high-dose combination inhaled steroids (up to 1000 mg flutica- Karegar-Borzi et al., 2015). sone or 1600 µg budesonide on a daily basis) and long acting beta Squill has been reported to exert anti-inflammatory, anti-oxidant, -agonists for at least 6 months. anti-bacterial, anti-cholinergic, and mucus secretion modulating ef- Inclusion criteria were patients aged 18–70 years, affected with fects. It is one of the origins of bufadienolide glycosides such as moderate to severe persistent asthma, FEV1 < 80% of the expected Scillaren A, scillirubroside, scilliroside, scillarenin, and proscillaridin A value, lack of pregnancy, lack of breastfeeding, not taking other herbal (Iizuka et al., 2001). Terness et al. demonstrated that bufadienolides medicines, lack of history of active peptic ulcer, cardiovascular disease such as proscillaridin A have a potent T-cell suppressive activity. This (including heart block), or renal disease, no concomitant use of an suppressive activity is more than 16,000 times stronger than cortisol anticoagulant, and non-smoking. Exclusion criteria were patient's use and 250 times stronger than cyclosporine A or tacrolimus. of drugs that interfere with asthma treatment such as NSAIDs, recent Proscillaridin A is a bufadienolide that acts like immune-regulatory infections leading to hospitalization, or the patient's unwillingness to biomolecules (T cell regulatory substances) (Terness et al., 2001). In continue treatment. addition, some Drimia