Abstract
Chronic rhinosinusitis (CRS) causes long-term discomfort for patients, and due to the frequent relapses and dissatisfaction with current treatments, CRS patients pay more attention to herbal-traditional remedies nowadays. Nigella sativa seed has a special place in Traditional Persian medicine because of its therapeutic and clinical applications. Therefore, we decided to evaluate the effect of N. sativa seed extract on clinical symptoms of CRS patients. In a double-blind controlled clinical trial on CRS patients referred to otolaryngology clinics of Firoozgar and Amiralmomenin hospitals, all the patients used nasal drops of the N. sativa (drug) or sesame oil extract (placebo), and standard SNOT-22 questionnaire completed on days 0 and 28th of study. Data collected and statistical analysis performed by SPSS software. Level of significance was considered as P < 0.05. Out of 53 subjects (33 male and 20 female), 27 were assigned in the drug group and 26 in the placebo group. The mean SNOT-22 score on the 28th day was 19.08 ± 13.21 in the drug group, and in the placebo group, the mean was 37.15 ± 21.47 (P = 0.001). N. sativa extract was particularly effective in improving the feeling of pain, pressure or fullness, numbness and congestion in the nose, and reduction of bad breath. The results of our study indicated that the N. sativa seed nasal drop significantly improved the symptoms of CRS—especially, four major and one minor symptoms- and improved the quality of life of the patients.
Keywords: Chronic rhinosinusitis , Nigella sativa , SNOT-22 , Traditional persian medicine
Introduction
Zokam (Rhinitis) and Nazleh (catarrh) are two phrases in Traditional Persian medicine for diseases of the nose which have a common origin. Avicenna (Famous Iranian scientist and physician) considered the origin of both diseases to be a substance of the nose [1]. Zokam is what that is poured into the nose and Nazleh is poured into the lower parts [1–3]. In the book of Exir, the phrase of "mother of disease" has only been used for the two diseases of zokam, nazleh and digestive corruption [3]. Because this disease not only causes disease in the nose, throat and adjacent organs, it also causes various diseases in other organs such as the lung, stomach and intestine [2, 3]. With the review of new references (written and electronic), it becomes clear that zokam and nazleh have not been studied separately, and the clinical signs of zokam and cold nazleh are consistent with chronic rhinosinusitis in modern medicine [4, 5].
The new definition of rhinosinusitis is a group of disorders characterized by mucosal inflammation of the nose and paranasal sinuses. Chronic rhinosinusitis (CRS) is a group of disorders characterized by inflammation of the nasal mucosa and paranasal sinuses that last for at least 3 months [6]. About 16% of adults in the United States suffer from rhinosinusitis annually [7], which imposes direct and indirect costs. It has been stated that $ 3.39 million per year has been spent for rhinosinusitis treatment and $ 3.8 billion has been spent for indirect costs because of absence from work [8]. It disrupts patients' daily work mentally and physically [9]. In a meta-analysis study, the rate of Rhinosinusitis in Iran was reported about 53%, therefore, the prevalence of this disease in Iranian people is high [10]. It is also estimated that approximately 5000 of these patients are undergoing surgery annually due to lack of response to medical treatments [11]. Despite acute rhinosinusitis, the role of bacteria in CRS has not been established. The fact that bacteria may be involved in different types of CRS with different mechanisms has led to the use of antibiotics in the treatment of this disease locally and systemically [6]. Long-term use of antibiotics in addition to increasing treatment costs may increase the likelihood of drug-related complications. Long-term use of topical steroids to reduce nasal mucosal inflammation, especially in dry climates, can cause nasal bleeding (Epistaxis) [12]. Despite all drug treatments and because of no improvement in symptoms, a number of patients choose herbal or other forms of traditional remedies in CRS [13]. Various medicinal plants have been used in studies, including: Rumex patientia (Garden patience), Ecballium elaterium (Squirting cucumber), Stachys schtschegleevii (Poulk), Pelargonium sidoides (African geranium) [14]. In the Traditional Persian medicine references, one of the therapies used in the treatment of zokam and Nazleh is N. sativa seed, which its different combinations has been used in a variety of ways, including odor, smoke and oil composition [13]. This plant had been used in the treatment of diseases such as asthma, bronchitis, diabetes, eczema, and fever. These effects are due to the presence of thymoquinone in this plant [15]. Also it is one of the most common herbal medicines in the clinical treatment of Rhinosinusitis is due to its anti-inflammatory, anti-oxidantanti, histaminic, antimicrobial, analgesic, and immunomodulator activities [16]. To best of our knowledge, no structured studies have been conducted on the effects of N. sativa seed extract on the recovery of CRS symptoms; hence, we studied the effect of nigella seed oil on the symptoms of CRS.
Methods
The proposal of this study was approved by the Medical Ethics Committee of Shahid Beheshti University of Medical Sciences, with the code no.7872/400. This study was a randomized double-blind clinical trial to evaluate the efficacy of nigella seed oil on CRS cases referred to ENT clinics at Firoozgar hospital (in Tehran) and Amiralmomenin hospital (in Rasht). Inclusion criteria included age over 15 years, having at least two major rhinosinusitis symptoms, or one major symptom and 2 minor symptoms, more than 12 consecutive weeks of rhinosinusitis and presence of disease evidences in CT scan of paranasal sinuses and/or sinonasal endoscopy. Exclusion criteria were pregnancy, use of corticosteroids in the last month, immunodeficiency, fever higher than of 37.8 °C and having extensive nasal polyposis (Lund-Mackay score more than 14 or stage 2 or 3 nasal polyposis in sinonasal endoscopy).
All the patients received complete explanation about the study and signed an informed consent form. Patients could freely exclude from the study if they did not tolerate the drug, became pregnant, had any side effects or had a fever above 38.5 °C while taking the drug, or did not want to continue the treatment. The sampling was done by Balanced Block Randomization method, so that before the study, a list of random numbers that were evenly divided into two groups provided by random allocation software was given to a third person. Each of them was placed in a separate envelope as listed, and closed. If the referred patient was eligible, one of the envelopes was given to the patient, and after filling out the forms the envelope would be opened and the patient would be assigned in one of the study groups and received the drug or placebo.
To produce N. sativa seed oil, Iranian N. sativa seed, originally from the Lordegan area of Chaharmahal va Bakhtiari province, was purchased from the market in Shahreza in Isfahan province, and was approved by the Herbarium Research Center of Traditional Medicine and Medical Affairs of Shahid Beheshti University of Medical Sciences. 300 g of N. sativa seed was powdered by an electric mill at 25 °C in the laboratory and immediately was mixed with 500 g of sesame oil. It was kept in the laboratory for a week in dark environment. Then it was filtered through a funnel and filter paper and poured into a completely matte white 10 cc droplet and sealed. It was kept in the same situation and was consumed by the patients twice daily. In the placebo group, the subjects received sesame oil extract by the same method. Indeed, in the intervention group, the subjects received mixed N. sativa and sesame extract and in the comparision or control group, the subjects received sesame extract, as the nasal drops with a similar dosage.
Sample size was calculated using SNOT-22 mean in a pilot study with 2% confidence interval and 80% power as 22 in each group and with predicting 15% drop-out of the subjects we considered 26 subjects in each group. The data were collected by examination and questionnaire. Form No. 1 contented the initial examination of the patients which was done by an otolaryngologist at the beginning of the study and it was repeated after the day 28th of the treatment. Demographic information was recorded in form No 2. Form No 3 or standard SNOT-22 questionnaire (Persian version) was filled out by patients on day zero and 1 week and 28 days after drug administration. We used SNOT-22 questionnaire that has been validated in a large-scale study [17] translated into Persian and validated in 2012 [18].
Statistical Analysis
The data were analyzed by SPSS version 21 software. Descriptive statistical methods including distribution table of mean and standard deviation index were used to describe individual characteristics of the study subjects. T-test was used to compare the mean of the results and hypothesis analysis. For qualitative variables, Chi-square test and Fisher test were used if needed. Level of significance was considered as P < 0.05.
Results
Out of 133 patients with CRS referred to the clinics of Firoozgar and Amir al-Momenin hospitals, 45 had extensive nasal polyposis, 5 did not have the age criteria, and 10 had used drugs interfering with the results, hence 73 subjects were eligible to participate in the study. Out of 53 subjects selected randomely (33 male and 20 female), 27 were assigned in the drug group, and 26 were assigned in the placebo group. During the study, 3 patients were excluded from the study, two from the drug group because of headache and one because of other drugs used in the course of study. In both groups, 50 patients completed the study course. In the drug group (24 patients), 11 (45.8%) were female, and 13 (54.2%) were male, and in the placebo group (26 patients), 8 (30.8%) were female and 18 (69.2%) were male. The mean age in the intervention group was 33.29 ± 12.57 years old (17–60 years old), and in the placebo group, it was 37.42 ± 14.84 years old(16–65 years old), and the difference was not significant according to t-test (P = 0.296).
All of the subjects had CT scan of paranasal sinuses, and the mean of Lund-MacKay score in the treatment group was 9.2 ± 4.3 and in the placebo group was 8.8 ± 5.1 (P = 0.93). On endoscopic nasal examination at the start of study, 14 and 16 subjects in case and placebo group, respectively, had only demonstrated mucosal inflammation and muco-purulent discharges (CRS without nasal polyposis), and 13 cases from each group (48.1% and 50% of cases and controls, respectively: P = 0.89) had grade 1 nasal polyposis that was mild in severity and confined to the middle meatus of the lateral nasal wall. Also, there was no significant difference in terms of age, sex, and history of medical conditions between the two groups.
The mean SNOT-22 score on day 0 in the drug group was 35.17 ± 14.17, and in the placebo group, the mean was 43.19 ± 21.15 (P = 0.12). The mean SNOT-22 score on the 28th day of the study was 19.08 ± 13.21 in the drug group, and in the placebo group, the mean was 37.15 ± 21.47(P = 0.001) (Fig. 1).
Fig. 1.
Comparison of the mean SNOT-22 questionnaire score in the two groups of drug and placebo on day 0 and day 28
In major symptoms such as pain or pressure in the face (P = 0.011), congestion or fullness in the face (P = 0.028), congestion or nasal obstruction (P = 0.025), pus or nasal discharge (P = 0.032), there was a significant difference between days 0 and 28 in the drug and placebo groups. Also, in minor symptoms on day 28, the difference between two groups was significant (P = 0.028). (Table 1). No side effect was reported in case or control groups. Endoscopic nasal examination at the end of the 4rd week revealed very mild inflammation/muco-purulent discharge in 9 cases (37.5%) and grade 1 polyposis in 6 patients (25%) from treatment group, while it showed inflammation/muco-purulent discharge in 14 subjects (53.8%) and grade 1 nasal polyposis in 12 cases (46.1%) from placebo group. All the patients were followed for 3–6 months after the completion of the treatment. All the patients in the case group (except 6) had no any significant sinonasal complaint that compelled them seeking physician or taking additional drugs except washing the nose with normal saline, one or two times a day. In contrast, in the placebo group, all of the subjects (except 4) obligated to receive other complementary drugs for relieving their sinonasal symptoms. Of course, we focused to evaluate the effect of N. sativa seed extract on clinical symptoms of CRS patients on the SNOT-22 findings.
Table 1.
Characteristics of qualitative variables at the start of treatment (day 0), with P value mentioned on days 0 and 28 in both groups
| Variable | Status | Drug | Plecebo | P | P |
|---|---|---|---|---|---|
| Count (%) | Count (%) | (day 0) | (day 28) | ||
| Gender | Female | 11 (45/83%) | 8 (30/77%) | 273/0 | – |
| Pain or pressure in the face | Yes | 12 (50/00%) | 15 (57/69%) | 586/0 | 0/011 |
| No | 12 (50/00%) | 11 (42/31%) | |||
| Congestion or fullness in the face | Yes | 17 (70/83%) | 18 (69/23%) | 902/0 | 0/028 |
| No | 7 (29/17%) | 8 (30/77%) | |||
| Congestion or nasal obstruction | Yes | 18 (75/00%) | 24 (92/31%) | 132/0 | 0/025 |
| No | 6 (25/00%) | 2 (7/69%) | |||
| Pus or nasal discharge | Yes | 19 (79/17%) | 23 (88/46%) | 456/0 | 0/032 |
| No | 5 (20/83%) | 3 (11/54%) | |||
| Decreased or no sense of smell | Yes | 16 (66/67%) | 18 (69/23%) | 864/0 | 0/153 |
| No | 8 (33/33%) | 8 (30/77%) | |||
| Pus in nose examination(endoscopy) | Yes | 12 (50/00%) | 16 (61/54%) | 412/0 | 0/459 |
| No | 12 (50/00%) | 10 (38/46%) | |||
| Headache | Yes | 13 (54/17%) | 14 (53/85%) | 982/0 | 0/294 |
| No | 11 (45/83%) | 12 (46/15%) | |||
| Fever | Yes |
0 0 |
0 0 |
0 – |
0 – |
| No |
– – |
– – |
|||
| Bad breath | Yes | 11 (45/83%) | 12 (46/15%) | 982/0 | 0/028 |
| No | 13 (54/17%) | 14 (53/85%) | |||
| Fatigue | Yes | 13 (54/17%) | 19 (73/08%) | 164/0 | 0/308 |
| No | 11 (45/83%) | 7 (26/92%) | |||
| Toothache | Yes |
– – |
– – |
– – |
– – |
| No |
– – |
– – |
|||
| Cough | Yes | 7 (29/17%) | 10 (38/46%) | 488/0 | 0/067 |
| No | 17 (70/83%) | 16 (61/54%) | |||
| Feeling pain or pressure or fullness in the ear | Yes | 3 (12/50%) | 3 (11/54%) | 000/1 | 0/491 |
| No | 21 (87/50%) | 23 (88/46%) |
Discussion
Rhinosinusitis is generally referred to inflammation of sinus and nasal mucosa, which is symptomatically similar to "zokam" and "nazleh" in Traditional Persian medicine. Nigella seed is an herbaceous plant that has been used to treat many diseases in Traditional Persian medicine, including zokam and nazleh [1]. Also, in the treatment of diseases such as asthma, bronchitis, diabetes, eczema, and fever [15] Cingi showed that there was no difference in histopathological changes in the treatment of rhinosinusitis patients between the antibiotic group and the thymoquinone group(a phytochemical compound in the N. sativa seed) [19]. But, Yoruk states that N. sativa may prevent histopathological changes in rhinosinusitis by reducing NO levels and may be used to treat rhinosinusitis [20]. To best of our knowledge, this is among the first structured study about the effects of Nigella seed extract on CRS symptoms. In the present study, the mean difference between day 0 and day 28 in the SNOT-22 questionnaire in the placebo group showed 4 points reduction, and the same difference in the drug group showed 16 points reduction. As we know, one way to measure outcomes is to determine the threshold for a particular outcomes measure that represents the smallest change in a measure or domain of interest that patients perceive as beneficial, termed the minimal clinically important difference (MCID) [19]. For several CRS-specific QOL measures, the MCID has been directly evaluated, as with the SNOT-22, and the published approximate MCID for SNOT-22 totally is ≥ 8.9 [21]. In a large study on patients with CRS who underwent nasal and sinus surgery in England and Wales, the least significant difference in the questionnaire score making the patient feel better was 9, which means that if reduction of this test score in patients before and after surgery is less than 9 points, they will not feel better [22]. In our study, the change of SNOT-22 scores in the placebo and drug groups showed 6 and 16 points reduction, respectively, that means unlike to the placebo, the drug (i.e. Nigella extract) had noticeable "clinical" effects in these patients, in addition to statistical significance. On the other hand, the mean comparison between the two groups was not significant at the beginning of the study, but the mean difference between the two groups was significant at the day 28th of the study (P = 0.001), and this difference remained significant after adjusting for baseline conditions (P = 0.001). This show the positive effects of Nigella seed oil extract on CRS patients quality of life. The obtained results were consistent with the results of the study by Snidvongs that was on corticosteroid nasal irrigations after endoscopic sinus surgery in the management of CRS [23]. Also, the results are in agreement with the results of the other studies on improving the quality of life measured by SNOT-22 in CRS patients [24, 25]. So that, Rezaeian in randomized clinical trial study, demonstrated that the N. sativa nasal spray in the treatment of chronic rhinosinusitis without polyp compared to sodium chloride spray resulted in a significant reduction in in the SNOT-22 score [26].
Patients also reported relieved pain or pressure during the intervention in the drug group, which was significant compared to the placebo group. One of the properties of the N. sativa seed is its anti-inflammatory effects. If the pain or pressure is due to nasal mucosal inflammation, it could be stated that the nigella seed has been effective in reducing inflammation. Analgesic effect is another property of N. sativa seed that the findings in our study support that [25, 27]. The feeling of congestion or fullness in the face also decreased significantly in the N. sativa extract group compared to the placebo group. This can be explained in several respects. First, because of the anti-congestive effects of N. sativa seed that has been emphasized in Traditional Persian medicine. Oysu showed that in the use of the intranasal N. sativa compared with sodium chloride solution for the management of elderly patients, although some of the symptoms did not differ in both treatment groups, but dryness, obstruction and crusting improved significantly [28] Also, in Traditional Persian medicine, the N. sativa seed is a strong evacuating drug due to its stiffness, infiltration and softness. It is also well absorbed, and causes a great deal of moisture to flow in the head [29], which along with its evacuating effect, it can reduce the feeling of fullness in the face. In our study, a decrease was observed in the feeling of congestion and blockage in the nose on day 28, which was statistically significant. Although our study findings showed that nigella seeds reduced symptoms such as: bad breath, loss of smell, pus in nasal examination, headache, fatigue, cough and feeling of fullness in the ear, in general, black seed oil was effective on four major and one minor rhinosinusitis symptoms. Due to the cost and also for radiation hazards, CT scans were not performed at the end of the treatment in the cases and controls, and they were followed up only by clinical examination and SNOT-22, and with sinonasal endoscopy. Of course, it would be better to take a sinonasal CT scan at the end of the third month and compare it with the CT scan of the start of the study, especially in the non-responsive or recurrent cases.
Conclusion
The results of our study indicated that the use of N. sativa seed oil as nasal drop can significantly improve the symptoms of CRS and improve the quality of life of these patients. N. sativa seed extract is particularly effective in improving the feeling of pain or pressure, congestion or fullness, numbness and congestion in the nose, reduction of bad breath. Overall, N. sativa seed was effective on four major and one minor symptoms of CRS.
Funding
This study was funded by Guilan University of Medical Sciences, Deputy of Research and Technology.
Compliance with Ethical Standards
Conflict of interest
None of the authors had any conflict of interest during this research.
Ethical Approval
All the participants had signed written informed consents and all of international/national ethical standards considered in this research.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Sina I, Hussein IA (1425) The canon of medicine. 4th and 5th centuries. research: Shamsuddin, Ebrahim. Institute of Al-Elmi Lel-matbuat, Beirut, AH, J 2, pp 432–434
- 2.Jorjani SE. Zakhire Kharazmshahi. Deputy of Research and Technology, Computerization Committee of Medicine and Health: Ministry of Health; 2008. pp. 376–378. [Google Scholar]
- 3.Cheshti M, Khan HA. Exire Aazam. Tehran: Institute of historical studies of islamic and complementary medicine; 2004. [Google Scholar]
- 4.Khosravi SA. Guide to health drugs. Tehran: Institute of historical studies of islamic and complementary medicine; 2007. p. 8. [Google Scholar]
- 5.Elahi H, Masroorchehr MR, Nemati S, et al. Historical applications of Nigella sativa L. (Black cumin) in the treatment of Zokam and Nazleh in Persian medicine. J Res History Med. 2014;3(1):11–20. [Google Scholar]
- 6.Flint PW, Haughey BH, Niparko JK, et al. Cummings otolaryngology-head and neck surgery e-book: head and neck surgery, 3-volume set. Amsterdam: Elsevier; 2015. [Google Scholar]
- 7.Anand VK. Epidemiology and economic impact of rhinosinusitis. Annals Otol Rhinol Laryngol. 2004;113(5):3–5. doi: 10.1177/00034894041130S502. [DOI] [PubMed] [Google Scholar]
- 8.Ray NF, Baraniuk JN, Thamer M, et al. (1999) Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol. 1999;103(3):408–414. doi: 10.1016/S0091-6749(99)70464-1. [DOI] [PubMed] [Google Scholar]
- 9.Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg. 2003;129(3):S1–32. doi: 10.1053/hn.2003.v128.amhn0312811. [DOI] [PubMed] [Google Scholar]
- 10.Andy SA, Sarookhani D, Tavirany MR. Prevalence of Sinusitis in Iran: a systematic review and meta-analysis study. Der Pharmacia Lettre. 2016;8(5):31–39. [Google Scholar]
- 11.Owings MF, Kozak LJ. Ambulatory and inpatient procedures in the United States. Vital Health Stat. 1998;13(139):1–119. [PubMed] [Google Scholar]
- 12.Rosenblut A, Bardin PG, Muller B, et al. Long-term safety of fluticasone furoate nasal spray in adults and adolescents with perennial allergic rhinitis. Allergy. 2007;62(9):1071–7. doi: 10.1111/j.1398-9995.2007.01521.x. [DOI] [PubMed] [Google Scholar]
- 13.Ardakani S, Farjadmand F. Makhzan al adviyeh and pointing to the scientific names of medicinal plants for the first time in a Persian Book. Publ Collab Univ Med Sci. 2018;3(4):508–504. [Google Scholar]
- 14.Ghazi-Moghadam K, Inançlı HM, Bazazy N, et al. Phytomedicine in otorhinolaryngology and pulmonology: clinical trials with herbal remedies. Pharmaceuticals. 2012;5(8):853–874. doi: 10.3390/ph5080853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Javidi S, Razavi BM, Hosseinzadeh H. A review of neuro-pharmacology effects of Nigella sativa and its main component, thymoquinone. Phytother Res. 2016;30(8):1219–1229. doi: 10.1002/ptr.5634. [DOI] [PubMed] [Google Scholar]
- 16.Mahboubi M. Natural therapeutic approach of Nigella sativa (Black seed) fixed oil in management of Sinusitis. Integr Med Res. 2018;7:27–32. doi: 10.1016/j.imr.2018.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009;34(5):447–54. doi: 10.1111/j.1749-4486.2009.01995.x. [DOI] [PubMed] [Google Scholar]
- 18.Jalessi M, Farhadi M, Kamrava SK, et al. The reliability and validity of the persian version of sinonasal outcome test 22 (snot 22) questionnaires. Iran Red Crescent Med J. 2013;15(5):404. doi: 10.5812/ircmj.7937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cingi C, Eskiizmir G, Burukoglu D, et al. The histopatho-logical effect of thymoquinone on experimentally induced rhinosinusitis in rats. Am J Rhinol Allergy. 2011;25:e268–e272. doi: 10.2500/ajra.2011.25.3703. [DOI] [PubMed] [Google Scholar]
- 20.Yoruk O, Tatar A, Keles ON, Cakir A. The value of Nigella sativa in the treatment of experimentally induced rhinosinusitis. Acta Otorhinolaryngologica Italica. 2017;37(1):32–37. doi: 10.14639/0392-100X-1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Smith KA, Orlandi RR. Chronic rhinosinusitis; outcomes of medical and surgical treatment. In: Flint Paul W, editor. Textbook of cummings otolaryngology head and neck surgery. 7. Philadelphia: Elsevier; 2020. pp. 2600–2623. [Google Scholar]
- 22.Hastan DF, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe—an underestimated disease. A GA2LEN study. Allergy. 2011;66(9):1216–23. doi: 10.1111/j.1398-9995.2011.02646.x. [DOI] [PubMed] [Google Scholar]
- 23.Snidvongs K, Pratt E, Chin D, et al. (2012) Corticosteroid nasal irrigations after endoscopic sinus surgery in the management of chronic rhinosinusitis. Int Forum Allergy Rhinol. 2012;2(5):415–421. doi: 10.1002/alr.21047. [DOI] [PubMed] [Google Scholar]
- 24.Farag AA, Deal AM, McKinney KA, et al. Single-blind randomized controlled trial of surfactant vs hypertonic saline irrigation following endoscopic endonasal surgery. Int Forum Allergy Rhinol. 2013;3(4):276–280. doi: 10.1002/alr.21116. [DOI] [PubMed] [Google Scholar]
- 25.Thamboo A, Manji J, Szeitz A, et al. The safety and efficacy of short-term budesonide delivered via mucosal atomization device for chronic rhinosinusitis without nasal polyposis. Int Forum Allergy Rhinol. 2014;4(5):397–402. doi: 10.1002/alr.21280. [DOI] [PubMed] [Google Scholar]
- 26.Rezaeian A, Amoushahi Khouzani S. Effect of Nigella sativa Nasal Spray on the Treatment of Chronic Rhinosinusitis Without a Nasal Polyp. Allergy Rhinol. 2018;9:1–5. doi: 10.1177/2152656718800059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hajhashemi V, Ghannadi A, Jafarabadi H. Black cumin seed essential oil, as a potent analgesic and antiinflammatory drug. Phytother Res Int J Devoted Pharmacol Toxicol Eval Nat Prod Deriv. 2004;18(3):195–9. doi: 10.1002/ptr.1390. [DOI] [PubMed] [Google Scholar]
- 28.Oysu C, Tosun A, Yilmaz HB. Topical Nigella sativa for nasal symp-toms in elderly. Auris Nasus Larynx. 2014;41(3):269–272. doi: 10.1016/j.anl.2013.12.002. [DOI] [PubMed] [Google Scholar]
- 29.Al-Qurashi A. Comprehensive in the medical industry. Cult Counc Abu Dhabi United Arab Emir. 2000;17:124. [Google Scholar]