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Medicinal benefits of Nigella sativa in bronchial asthma: A literature review

Nigella sativa L. (NS) seeds, known as black seed, is a spice and a traditional herbal medicine used in various diseases including bronchial asthma. This review aimed to assess the studies supporting the medicinal use of NS in asthma and to highlight future research priorities. Various medical databases were searched for the effects of NS and its active secondary metabolites in asthma inflammation and outcomes. There were fourteen preclinical studies describing multiple effects of NS in animal or cellular models of asthma including bronchodilation, anti-histaminic, anti-inflammatory, anti-leukotrienes and immunomodulatory effects. Furthermore, seven clinical studies showed improvements in different asthma outcomes including symptoms, pulmonary function and laboratory parameters. However, often these studies are small and used ill-defined preparations. In conclusion, NS could be therapeutically beneficial in alleviating airway inflammation and the control of asthma symptoms, but the evidence remains scanty and is often based on poorly characterised preparations. Accordingly, well-designed large clinical studies using chemically well characterised NS preparation are required.


Introduction
The seeds of the medicinal plant Nigella sativa L. (NS) are commonly used as a spice known as black seed. It also has traditional medical applications and considered to be a characteristic traditional herbal medicine for diverse diseases in Unani, Arabic, Prophetic and Indian traditional medicines (Ahmad et al., 2013). Popular ancient physicians such as Hippocrates , , , and Avicenna (980-1037 CE) reported various traditional therapeutic uses of NS (Botnick et al., 2012).
In the context of bronchial asthma and its symptoms, the Muslim scholar Imam Ibn Qayyim Al-Jawziyya (1292-1350 CE), author of the Prophetic Medicine, reported that NS aid in gasping and hard breathing (Abdullah, 2003). Avicenna (Avicenna, 1593). Nowadays, NS is still a traditional remedy for many illnesses such as cough and asthma in Arabia (Lebling and Pepperdine, 2006).
The Global Initiative for Asthma defined asthma as ''a heterogeneous disease, usually characterised by chronic airway inflammation. It is identified by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation" (Global Initiative for Asthma, 2017). The Global Asthma Report 2014 considered asthma as an epidemic disease probably affecting about 334 million people worldwide and becoming a global health priority (Global Asthma Network, 2014). In Saudi Arabia (with a population of 28 million), the prevalence of asthma is increasing and affects more than 2 million Saudis (Al- Moamary, 2012).
Asthma is initiated by multiple interactions between inflammatory cells and mediators. After an exposure to a triggering factor, inflammatory mediators are released from mast, macrophages, T-cells and epithelial cells. This cause attraction of other inflammatory cells mainly eosinophil into the pulmonary tissues. These causes lung injury, mucus hypersecretion and smooth muscle hyperactivity. Furthermore, at least 27 cytokines and 18 chemokines play a role in asthma pathophysiology (Koda-Kimble, 2009). Th2 lymphocytes cytokines [interleukin IL-4, IL-5, and IL-13] and Th1 cytokine interferon-gamma are the main ones to provoke allergy and asthma (Ngoc et al., 2005).
Generally, the key goals for asthma management are to reach a good control of symptoms and minimize future risk of exacerbations, airflow limitation and treatment adverse events. Assessment of asthma control level can be done using several tools (Bateman et al., 2008). The Asthma Control Test (ACT) is a global validated numerical tool for the assessment of asthma control which is also commonly used by health care providers in Saudi Arabia (Al- Moamary, 2012). Future risk can be assessed by pulmonary function testing, particularly the forced expiratory volume in one second (FEV1) (Bateman et al., 2008).
From a global clinical perspective, achieving asthma control is considered to be suboptimal regardless of the availability of conventional treatments (Demoly et al., 2012;Price et al., 2014). Poor adherence to asthma medications is one of the factors leading to suboptimal asthma control (Haughney et al., 2008;Horne et al., 2007). Common medication-related reasons for non-adherence include difficulties with inhaler techniques, the complex course of therapy, adverse events, and cost of medications (Bateman et al., 2008;Dima et al., 2015). In Saudi Arabia, a survey of adult asthmatics found that asthma attacks were highly associated with patients on current asthma medications (Moradi-Lakeh et al., 2015). The Global Asthma Physician and Patient Survey reported that 76% of patients and 81% of physicians consider that new treatment options are required (GAPP, 2005). The introduction of novel treatment strategies (such as ''add-on" treatments) is a key step for better asthma control (Lommatzsch and Stoll, 2016).
Asthma patients tend to use herbal medicines as one of the common therapies of complementary and alternative medicine (Slader et al., 2006). However, these therapies often have insufficient evidence for their effectiveness in asthma. In Saudi Arabia, a questionnaire type study was done by Al Moamary (2008) in 200 asthmatic patients. He found that NS is one of the most commonly non-standard therapies used by 10% of the patients.
In this review, we aimed at exploring and assessing the relevant pre-clinical and clinical studies supporting the use of NS in patients with asthma, and evaluating the current evidence to highlight future research priorities.

Methods
A literature search for scientific studies published in electronic databases (PubMed, Science Direct, Scopus, and Google Scholar) was done using the terms Nigella sativa, Black seed, Thymoquinone and (their pharmacological effects) on asthma. Studies were searched for electronically between the years 1990 and 2017. Retrieved studies were assessed and the data was categorised into preclinical and clinical studies.

Results
At least nineteen preclinical studies and seven clinical studies reported the effects of NS in asthma. Details of the retrieved studies are summarised in the following.
Generally, these studies used animal models sensitised with ovalbumin or isolated Guinea pig trachea. Some studies used cellular models such as human granulocytes or animal mast cells. However, these studies had limitations such as the variability of NS preparations used between most them, and absence of control group in some studies (Table 1).

Clinical studies of Nigella sativa in patients with asthma
Seven clinical studies showed a potential efficacy of NS on asthma outcomes and biomarkers. Three Randomised Double-Blinded Placebo-Controlled Clinical Trials (RDBPCT) and two Randomised Single-Blinded Placebo-Controlled Clinical Trials (RSBPCT) using NS crushed seeds powder or oil/aqueous extract, showed an improvement in clinical symptoms and pulmonary function test in adult asthmatics (Boskabady et al., 2007;Kalus et al., 2003;Kardani et al., 2013;Koshak et al., 2017;Salem et al., 2017). In addition, a reduction of blood eosinophilia was found in RDBPCT by Koshak et al. (2017). Also, a decrease in total serum IgE and FeNO, and an increase in serum INF-gamma cytokine were shown in the RSBPCT trial of Salem et al. (2017).
A Randomised Double-Blinded Clinical Trial (RDBCT) showed a short bronchodilatory effect in patients with asthma after administration of a single dose of NS (Boskabady et al., 2010). Two studies used NS in combination with other treatments showed an improvement in ACT and PFT scores (Al Ameen et al., 2011;Kardani et al., 2013) (Table 2).
However, these clinical trials appeared to have some important limitations (Table 2). In many of these studies, the standard of design was poor as three studies only were RDBPCT. The phytochemical characterisation of the investigational NS product was not shown in many studies. The sample size was comparatively small in most studies. The largest trial by Koshak et al. (2017) included 80 adult asthmatic patients. The measured outcomes were generally limited to symptoms or pulmonary function in several studies.
Therefore, there is a need for a longer, larger and high standard multicentre clinical trial (more than 80 asthmatic patients) with phytochemically well-characterised NS product. Also, to use validated asthma control measurement tools with consideration of additional asthma outcomes and biomarkers such as FeNO, Sputum eosinophils, total blood eosinophils, total serum IgE, allergen-specific IgE and urinary LTE4 (Szefler et al., 2012). Additionally, measuring serum inflammatory cytokines may be worth considering, since asthma is regulated by multiple inflammatory cytokines and some were associated with asthma control (Akiki et al., 2017).

Conclusion
This literature review showed that various preparations derived from Nigella sativa have a potential role for the clinical use in asthma. Preclinical studies of NS preparations showed bronchodilation, anti-histaminic, anti-inflammatory, anti-leukotrienes and immunomodulatory effects in animal or cellular models of asthma. Clinical studies of NS preparations showed an improvement of asthma symptoms control, lung function and asthma biomarkers. However, these studies have study design limitations and limited phytochemical characterisation of NS preparations used. Consequently, the current clinical evidence for the use of NS in patients with asthma is evolving in strength. In future, larger, longer, well-designed clinical trials including additional biomarkers and using phytochemically characterised NS preparation are required for assessing the clinical use of NS in asthma. Eventually, NS may offer a cost-effective and clinically proven effective add-on therapeutic option for asthmatics with fewer side, which may be used as integrative medicine within the Saudi healthcare system and beyond. Fallahi et al. (2016) a-hederin