Medicinal Plants for Viral Respiratory Diseases: A Systematic Review on Persian Medicine

Introduction Many medicinal plants have been introduced in Persian medicine references for various respiratory disorders. Considering the growing interest in herbal medicines, this review aimed to introduce medicinal herbs recommended by Persian Medicine (PM) references for respiratory diseases and to discuss their activity against respiratory viruses. Methods The medicinal plants recommended for respiratory disorders were extracted from the main PM textbooks. Subsequently, their activity against respiratory viruses was systematically investigated via queries of scientific databases. Results Searching PM references for medicinal plants used in the management of respiratory disorders yielded 45 results. Of them, 18 possess antiviral activity against respiratory viruses. There were 29 in vitro studies (including studies on human cell lines) and 5 in vivo studies. Conclusion This research demonstrated that many of the medicinal plants mentioned for the respiratory diseases in PM have considerable activity against respiratory viruses. However, human studies regarding the reported medicinal plants are scarce.


Introduction
Viral respiratory infections are one of the most prevalent causes of medical consultations globally [1]. Known for a variety of clinical pictures, from self-limited upper respiratory tract diseases to life-threatening ones [2,3], these infections deeply infuence the quality of life and have a noticeable economic burden [4][5][6]. Additionally, the World Health Organization reports respiratory infections as the main reason for mortality among all infectious diseases [7]. Respiratory syncytial virus, infuenza virus, metapneumovirus, parainfuenza viruses, adenoviruses, bocaviruses, rhinoviruses, and coronaviruses are respiratory viruses that are associated with epidemic or endemic infections in all continents [8]. Moreover, several viruses of the herpesvirus family, including cytomegalovirus, herpes simplex, varicella-zoster virus, human herpesvirus 6, and Epstein-Barr virus, may also be responsible for respiratory disease in immunocompromised individuals [8,9]. Te world is experiencing the third pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the present century [10]. Tis novel coronavirus disease (COVID-19) is currently the most serious concern for the international community. It is a viral respiratory disease for which no efective treatment has yet been identifed [11].
Statistical analysis of studies related to the SARS 2002 outbreak indicated that the integration of traditional Chinese medicine (TCM) with conventional medicine could reduce morbidity and mortality rates as compared with mere conventional therapy [12]. Additionally, various traditional medical systems have brought up the issue of respiratory infections and related treatments [13][14][15][16][17]. Based on the humoral theory, Persian Medicine (PM) is an ancient medical system with multiple options for treating diseases and managing complications [18][19][20][21]. Specifcally, numerous remedies have been reported in PM references for the treatment of various respiratory disorders, including asthma and pneumonia [22]. Additionally, there are several plausible mechanisms for the antiviral activity of these medicinal plants. Figure 1 shows some of the proposed mechanisms, which may interrupt the coronavirus replication cycle [23][24][25]. Using herbs rather than contemporary drugs in COVID-19 therapy may have a wide variety of benefts and advantages, from a cheaper price and better worldwide availability to lesser adverse events, a better attitude of the general population towards them, and a decreased demand for conventional drugs and hospitalization [26][27][28].
Considering the global spread of viral respiratory infections, especially COVID-19, and the lack of any proven treatment in many cases, this research aimed to introduce medicinal plants recommended for respiratory diseases in PM and to review their activity against respiratory viruses according to current biomedical literature.

Methods
Ketab al-Hawi f al-Teb (Continens) by Rhazes (9 th and 10 th centuries), Qanun f al-Ṭeb (Canon of Medicine) by Avicenna (10 th and 11 th centuries), Tebb-e Akbari (Akbari's Medicine) by Mohammad Akbar Arzani (18 th century), Exire Azam (Te Great Panacea) by Nazem Jahan (18 th and 19 th centuries), and Makhzan al-Advieh (Storehouse of Medicaments) by Aghili Shirazi (18 th century) are the most important and comprehensive textbooks of PM. Tey also comprise the references in the Ph.D. program for PM in Iran. Chapters related to respiratory disorders (respiration or tanafos; lung or shosh, riyah; asthma or rabv; dyspnea with rapid and shallow breathing, cough or sorfeh, sputum or nafth in Persian) were selected and carefully searched for recommended medicinal plants.
Te suggested medicinal plants were searched for their scientifc and common names in English. Subsequently, medical English and Persian databases including MEDLINE, Scopus, Iranmedex, SID, Magiran, Web of Science, and Google Scholar were systematically searched. Each herb was searched along with keywords including "antivirus," "coronavirus," and "COVID-19." Two researchers independently screened the articles, reading their abstracts and titles to identify potentially eligible studies. Tereafter, full texts were obtained and read to determine the fnal included articles. In addition, the references of the retrieved articles were manually searched to identify other potentially eligible studies. Papers published in languages other than English or Persian were excluded. In addition, review articles and conference papers were not   Evidence-Based Complementary and Alternative Medicine included in this systematic review. Moreover, research studies on nonrespiratory viruses and viruses not pathogenic for humans were excluded from the study. Any disagreement was resolved by discussion. Te extracted data included plant scientifc name, Persian name, English common name, used part of the herb, studied antiviral efect, and study type (including in-vitro, animal, and clinical). It should be noted that each plant's main compounds and route of traditional administration were added based on the PDR for herbal medicines (3 rd edition) [29] and Makhzan al-Advieh (Storehouse of Medicaments) by Aghili Shirazi, respectively.

Results
Forty-fve medicinal plants recommended for respiratory diseases by PM resources were extracted in the frst phase of the study. Overall, eighteen of the herbs recommended by PM resources for respiratory diseases have evidence regarding activity against viruses that can cause infectious respiratory disorders. Most of the research studies in this regard were in vitro studies. In addition, most of the mentioned plants were reported to act against infuenza viruses (Table 1).

Discussion
Te viral respiratory infection outbreaks promoted the conduct of studies with the purpose of evaluating novel medications, especially natural-based remedies, resulting in the discovery of potential drugs. Te efectiveness of various herbs is published as the result of studies designed as case series, clinical trials, and systematic reviews [58][59][60]. Tese research studies encouraged further investigations to elucidate the potential of herbal compounds to manage coronavirus infections [61][62][63]. According to previous records regarding SARS 2002, TCM in combination with routine drugs has been far more efective than conventional therapy alone [12,60,61]. TCM physicians prescribed herbal remedies, which are known for their anti-infammatory, antiviral, and immunomodulatory properties, for better management [12]. Studies have shown that these medicinal plants decrease the mean needed dosage of medications such as corticosteroids in severe cases and also diminish the adverse efects of some drugs. Tere are some reports that using corticosteroids for managing viral respiratory infections may lead to some adverse events (e.g., the development of fungal infection and femoral head necrosis). According to the results of 24 trials used in a meta-analysis, no long-term side efects due to taking high-dose corticosteroids were reported in integrative treatment (i.e., a combination of herbal drugs and conventional treatment) [61,64].
It should be noted that some ancient medical systems, such as PM, TCM, and Unani medicine, have individualized approaches (phenotype-based personalized medicine) to treatment. Traditional practitioners consider gender, age, season, comorbidities, and many other patient characteristics to diagnose and manage diferent diseases [12,[65][66][67].
Human society is currently struggling with the COVID-19 pandemic, and no efcient drugs have been identifed as of yet. Terefore, emphasis is placed on preventive measures and symptomatic therapies [68]. Regarding this, numerous research studies have been done to evaluate the safety and efcacy of preventive, therapeutic, supportive, or rehabilitative medicaments recommended in various traditional medical systems [15,24,69,70]. Te emphasis of the World Health Organization on the integration of traditional, complementary, and alternative medicine in the conventional health system and the growing interest in natural products for the management of diseases highlight the necessity of studies on diferent aspects of traditional medicines to reinforce the scientifc evidence basis for natural remedies [19,71].
Several research studies have previously been done to assess the efcacy of medicinal herbs reported in folklore or traditional medicine systems of diferent countries against various viral or bacterial respiratory infections [14]. A study in Guatemala assessed the antibacterial efect of 68 herbs traditionally applied for respiratory ailments. According to the results, 28 medicinal plants possessed inhibitory efects on one or more gram-positive bacteria, including Streptococcus pneumonia, Staphylococcus aureus, and Streptococcus pyogenes [72]. Another study investigated the antiviral properties of 44 Chinese herbs against the respiratory syncytial virus and demonstrated 27 medicinal plants with antiviral activity against this virus [73].
Te current study reviewed the antiviral properties of medicinal plants recommended for respiration disorders in PM. Te antiviral efects of 18 (out of 45) herbs have been investigated and confrmed by experimental studies to date. Only some of the studies were performed on humans, while preclinical studies comprised the majority of the reports. Te mentioned plants for respiratory disorders have antiviral activity as well. Tey have several other benefcial efects for patients with viral respiratory infections, including COVID-19 [23,[74][75][76][77][78] (Figure 2).
Among these research studies, the efcacy of Glycyrrhiza glabra, Urtica dioica, and Nigella sativa against coronaviruses has been confrmed [33]. Tese herbs not only possess antiviral activity but can also be used to alleviate symptoms associated with respiratory infections. For example, Glycyrrhizin, an active component (a triterpenoid saponin) of Glycyrrhiza glabra (licorice) root, has shown remarkable antiviral efects against coronavirus isolated from patients with SARS. Virus replication is inhibited when a nitrous oxide donor is added to the culture medium, and it was shown that glycyrrhizin induces nitrous oxide synthase in Vero cells. Also, glycyrrhizin lowers the expression of viral antigens and is able to inhibit the adsorption and penetration of the virus [33]. Moreover, this herb has exhibited antitussive activity on sulphur dioxide-induced cough in experimental rats [79]. In another study, rats with carrageenan-induced paw edema were treated with the hydroalcoholic extract of Glycyrrhiza glabra root. Its potent anti-infammatory activity has been shown. Tis extract inhibited the migration of leukocytes dose-dependently, with anti-infammatory efects comparable to indomethacin [80].
An in vitro study demonstrated that Nigella sativa extract has antiviral action by preventing coronavirus replication [57]. Tymoquinone, an important constituent of Evidence-Based Complementary and Alternative Medicine  Evidence-Based Complementary and Alternative Medicine 5 Nigella sativa, has been assessed for its antitussive property in guinea pigs. Tis constituent signifcantly subsided the cough induced by the nebulized solution of citric acid (20%). Additionally, pretreatment with naloxone leads to suppression of its antitussive efect, indicating stimulation of opium receptors as the mechanism [81]. Furthermore, analgesic and anti-infammatory activities of the aqueous extract of Nigella sativa have been confrmed in rats via carrageenan-induced paw edema and hot plate reaction time, respectively [82]. Among herbs that have been recommended in PM references for respiratory disorders, the activity of 18 medicinal plants against respiratory viruses has been confrmed to date. Further studies are needed to evaluate whether other suggested medicinal plants have any efect against respiratory viruses or not. Further clinical studies should be considered a very important step towards the utilization of these plants in clinical practice. Also, further studies are necessary to compare the efciency and safety of these herbs with conventional antiviral drugs. Another limitation of this research was the inclusion of only English and Persian papers.

Conclusion
Due to challenges with efcacy and safety, high costs, and limited worldwide availability of conventional treatments, the use of herbal medications for the management of viral respiratory infections is increasing. Tis systematic review showed antiviral activity (especially against infuenza viruses and coronaviruses) for a signifcant portion of the medicinal herbs recommended for respiratory disorders in PM. However, not enough investigations have been conducted to confrm the efcacy of several of these plants on viral respiratory infections. Lack of or scant clinical studies is the main challenge in this regard; more vigorous research is suggested.

Data Availability
Te data used to support the fndings of this study are included within the article.

Ethical Approval
An ethics statement is not applicable because this study is based exclusively on published literature.  Evidence-Based Complementary and Alternative Medicine 7

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Mahdie Hajimonfarednejad was in charge of conceptualization, methodology, investigation, writing the review, and editing; Mohadeseh Ostovar handled methodology, investigation, writing the review, and editing; Fatemeh Sadat Hasheminasab was in charge of methodology, investigation, and writing the original draft; Mohammad Ali Shariati handled investigation, writing the review, editing, and visualization; Muthu Tiruvengadam was in charge of investigation, writing the review, editing, Visualization; Mohammad Javad Raee was in charge of conceptualization, methodology, resources, writing the review, editing, and supervision; and Mohammad Hashem Hashempur handled methodology, investigation, writing the original draft, visualization, and supervision.