key: cord-0922999-clbvmx9g
authors: Karimi, Mehrdad; Zarei, Azadeh; Soleymani, Samaneh; Jamalimoghadamsiahkali, Saeidreza; Asadi, Asmaa; Shati, Mohsen; Jafari, Mohieddin; Rezadoost, Hassan; Kordafshar, Gholamreza; Naghizadeh, Ayeh; Mardi, Raefeh; Namiranian, Parva; Khamechi, Seyed Peyman; Ansari, Narges; Adel Mehraban, Mohammad Sadegh; Aliakbarzadeh, Hananeh; Khanavi, Mahnaz; Esmaealzadeh, Niusha; Moravveji, Alireza; Salahi, Mehrdad; Khoi, Maryam; Razzaghi, Reza; Banafshe, Hamid Reza; Alizadeh, Mostafa; Akhbari, Marzieh; Atharizadeh, Mina; Izadikhah, Akram; Elsagh, Mahin; Hossein Zade Ghahnavieh, Mahdi; Eghbalian, Fatemeh; Vanai, Azam; Izadi, Hossein; Moravej, Seyed Ali Al‐hadi; Jazayeri, Seyede Ferdos; Bayat, Houman; Emadi Koochak, Hamid; Zargaran, Arman
title: Efficacy of Persian medicine herbal formulations (capsules and decoction) compared to standard care in patients with COVID‐19, a multicenter open‐labeled, randomized, controlled clinical trial
date: 2021-10-04
journal: Phytother Res
DOI: 10.1002/ptr.7277
sha: aedea2b18f746eef5e52e4670f268fe927be4055
doc_id: 922999
cord_uid: clbvmx9g

Persian medicine has recommended clinical experiences and proper herbal remedies for prevention and treatment of microbial infections and respiratory diseases. An open‐label, randomized, controlled, multicenter trial was conducted at five hospitals in Tehran and Isfahan provinces of Iran on 358 hospitalized adult patients. A total of 174 patients received standard care and 184 received herbal remedies (polyherbal decoction every 8 hr and two herbal capsules every 12 hr) plus standard care for 7 days. The primary clinical endpoint was the duration of hospital stay, and secondary outcomes were clinical improvement of symptoms based on self‐assessment questionnaire. Results demonstrated that these natural decoction and capsules treatment plus routine care significantly decreased duration of hospital dyspnea (3.291 day vs. 6.468 days), accelerated clinical improvement, and decreased symptoms such as dry cough, dyspnea, muscle pain, headache, fatigue, anorexia, chills, runny nose, sputum cough, and vertigo in the treatment group compared with standard‐care group. Significant effects of these polyherbal formulations on improving the symptoms of COVID‐19 could be incredibly promising for managing this pandemic with acceptable tolerability.

Since December 2019, a novel coronavirus disease (COVID-19) has caused outbreak of pneumonia in Wuhan, Hubei province, China (Guan et al., 2020) . The rapid spread of COVID-19 was identified as a pandemic and public health emergency of international concern (PHEIC) by the World Health Organization (WHO, 2020) on March 11, 2020 (Huang, Wei, Hu, Wen, & Chen, 2020) . Shi et al explained that bats are natural hosts of COVID-19, and full sequence of the COVID-19 genome in an infected patient is 96% similar to coronavirus in bats (Zhou et al., 2020) .

This strain of coronavirus also belonged to the same family of viruses that lead to Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) (Yang, Islam, Wang, Li, & Chen, 2020) . The most common symptoms related to COVID-19 infection are fever, fatigue, loss of appetite, dry cough, and dyspnea, whereas less common symptoms are diarrhea, nausea, vomiting, rhinorrhea, chest pain, congestion, malaise, arthralgia, myalgia, headache, and sore throat (Abebe, Dejenie, Shiferaw, & Malik, 2020) . Since the beginning of the spread, more than 57,639,631 confirmed COVID-19 patients have been identi- . Natural products, their derivatives, and herbal extracts have potential activities in the viral infections therapy (Rosales-Mendoza, 2020). Significant antiviral activity of glycyrrhizin in Glycyrrhiza glabra against SARS coronavirus has been confirmed in various studies (Ahmad, Rehman, & Alkharfy, 2020) . In this regard, usage of traditional, complementary, and alternative medicine to reach new approach for treatment is promising. Persian medicine is one of the oldest traditional medical system in the world that dates back to more than 7,000 years ago (Soleymani & Zargaran, 2018) . Persian medicine has obtained important clinical experiences, as well as efficient and proper herbal formulations based on patients' symptoms on the prohibition and treatment of microbial infections and respiratory diseases (Walsh, 2021; Yingwen, 2021) . Thus, it could be an alternative strategy to overcome viral transmission and prevention and treatment of . Regarding this strategy, this multicenter open-labeled, randomized, controlled, clinical study was designed to evaluate the efficacy of three herbal formulations (polyherbal decoction and two capsules) based on Persian medicine in hospitalized patients with COVID-19.

This is a multicenter open-labeled, randomized, controlled clinical trial and five centers participated in this trial from March 2020 to July 2020 (Table 1) . Patients with COVID-19 based on CT scan, oxygen saturation, and RT-PCR test as well as visit of an infectious disease specialist were enrolled in the study. 

To reach a formulation based on Persian medicine principals, all the monographs (about 1700 monographs) in the book of Makhzan al-Advieh (the Storehouse of Medicaments) were studied to find someones most likely to have been influential on COVID-19 based on Persian medicine principals (Aghili khorasani Shirazi, 2006) . This book is a comprehensive Persian encyclopedia of materia medica, which was written in the 19th century. It is available in a database called Universal Natural Product Resource (UnaProd, 2020) (http://unaprod.com). Initially, a list of 101 diseases and symptoms that resembled COVID-19 infection were selected from Iranian traditional medicine General Ontology (IrGO, 2020) knowledge base (http://ir-go.net). Additionally, a list of 77 drug actions that included those effective on the selected diseases, or associated with reinforcement of the body, and tonifying of lung and its functions were prepared. Subsequently, monographs that were effective on one or more of the selected diseases and actions were extracted via text mining methods in R. Also, scientific names of these herbs were extracted from UnaProd and then searched in PubMed in combination with relevant keywords to find mechanism of actions according to current science.

Finally, by meeting Persian medicine and current medical science, two capsules and one decoction were formulated for this study.

In the next step, adequate amount of several plants was purchased from a traditional herbal market in Tehran. These plants were identified and approved by botanists at the Herbarium Center of the School of Pharmacy, Tehran University of Medical Sciences (Table 2) .

For preparation of capsule 1, first, rhizome of Rheum palmatum L., root of G. glabra L., and fruit peel of Punica granatum L. were mixed in a ratio of 0.5:1: 1 and pulverized with an electric mill. They were then extracted by maceration using 4 L of 70% of hydroethanolic solution (70:30 vol/vol ethanol: water) every 48 hr for three times. Then, the extract was separated and concentrated using rotary evaporator as much as possible. It was put in a vacuum oven until maximum drying.

Afterward, lyophilized powder was prepared via a freeze dryer. The final product was mixed with starch (Merck, Germany) as filler and was packaged in 500-mg capsules. It was determined that every capsule has lyophilized powder of hydroalcoholic extract of one-gram raw material of G. glabra and P. granatum and 0.5-g raw material of R. palmatum, and the rest of each capsule was filled by starch as filler.

To prepare capsule 2, seed of Nigella sativa L. was powdered and packaged in 500-mg capsules.

Another remedy was prepared as a polyherbal decoction. Each package contains 7 sachets of a mixture of 10 g of each following powdered herbs (each sachet for one day): Matricaria chamomilla L., Zataria multiflora Boiss., G. glabra L., Ziziphus jujuba Mill., Ficus carica L., Urtica dioica L., Althaea officinalis L., and Nepeta bracteata Benth.

Every day, one sachet was decocted for 1 hr in 900 cc of water and then filtered and used three times a day (each time about 300 cc).

Total phenolic content was determined via spectrophotometer based on the Folin Ciocalteu's method, and absorbance was evaluated against the prepared blank at 765 nm. The calibration curve was plotted using standard gallic acid. The total phenolic content was represented as mg gallic acid per gram of product (Marinova, Ribarova, & Atanassova, 2005) . Quercetin was applied as standard to construct the standard curve.

Total flavonoid content was expressed as mg quercetin equivalent per gram of product (Beketov, Pakhomov, & Nesterova, 2005 

After explaining the study procedure to eligible patients and obtaining their informed consent, 358 hospitalized patients were selected (161 women and 197 men) who were positive on RT-PCR, had pneumonia confirmed by chest imaging and had an oxygen saturation of 93% or lower on room air.

The patients were randomly assigned into two groups of treatment and control by a third person through a computer program with block randomization method with four size blocks. The random sample number is generated and each patient will be assigned a number.

As many as 174 patients received routine interventions according to the instructions of the Iranian Ministry of Health (2020) such as azithromycin, hydroxychloroquine, KALETRA ® (lopinavir/ritonavir), and 184 received herbal remedies (decoction every 8 hr and capsules every 12 hr) plus routine interventions for 7 days. Demographic information of the patients is explained in more details at baseline in Table 3 . Patients were assessed on days 0, 3, and 7 by physicians who were specialists in Persian medicine.

Inclusion criteria are age range of 18 to 75 years in both genders with one or more of the following symptoms: acute respiratory disease (ARI); RR > 30; oxygen saturation < 93%; pulmonary infiltration in were expired. Six patients in standard care group were discharged from the hospital with personal consent and did not continue the treatment.

Primary endpoint

Significant statistical differences were detected in terms of duration of hospital stay between the two groups (p < .001, hazard ratio = 0.3).

Patients in the treatment group had a shorter stay in the hospital than those in the standard-care group (median, 3.291 days vs. 6.468 days, respectively).

Seven days after the onset of interventions, fever reduction was sta- Figures 3 and 4) . However, the decrease in chest pain, laryngeal pain, sore throat, diarrhea, and cramp

were not significant at day 7 between the two groups (Table 4 and (Hamauzu, Yasui, Inno, Kume, & Omanyuda, 2005) . In a study con- PFT indices in sulfur mustard-exposed patients (Khazdair, Ghorani, Alavinezhad, & Boskabady, 2020) .

Major constituents of the flowers of M. chamomilla, once called chamomile, include flavonoids (apigenin, luteolin, and quercetin) and essential oils (chamazulene and α-bisabolol) (Gupta, Mittal, Bansal, Khokra, & Kaushik, 2010) . Several studies showed that chamomile possessed strong anti-inflammatory activity. The freeze-dried extracts of chamomile repressed leukocyte infiltration and inflammatory effect (Al-Hindawi, Al-Deen, Nabi, & Ismail, 1989) . Efficacy of α-bisabolol on the inflammatory response was evaluated by affecting on leukocyte activity and NO production in systemic infection experimental model in mice (Cavalcante et al., 2020) . Immunomodulatory effects of chamomile heteropolysaccharides are attributed to the activation of immunoregulation cells of peripheral blood, initiation of immunostimulatory effects of erythrocytes (macrocytes), and heightened sensitivity of helper cells (Gupta et al., 2010) . Also, using chamomile essential oil topically improved patients with genital herpes (Koch, Reichling, Schneele, & Schnitzler, 2008) . According to various studies in folk medicine of different countries, chamomile is used to treat respiratory diseases such as treatment of influenza, colds, and cough (Kültür, 2007 (Joseph, Aravind, Varghese, Mini, & Sreelekha, 2012) . In a study of ethnomedicine in Pakistan, it was regarded as an effective plant for respiratory problems, especially cough and fever caused by colds (Aziz et al., 2016) . Therapeutic effects of pomegranate juice in various inflammatory diseases such as rheumatoid arthritis, IBD, and in animal models of respiratory diseases, suggesting its usage in the treatment of chronic inflammatory diseases (Danesi & Ferguson, 2017) . Moreover, pomegranate extract has dem- (Xu, Li, & Cong, 2005) . Luo et al. in 2009, demon- strated that hydroethanolic extract of 70% Chinese rhubarb can strongly function against SARS-CoV 3CL protease (Luo et al., 2009) . In another study, anthraquinone emodin and kaempferole glycosides in Chinese rhubarb considerably reduced the symptoms of SARS-CoV by inhibiting 3a-channels (Schwarz et al., 2012) . Moreover, with block SARS-CoV spike protein and angiotensin-converting enzyme 2 (ACE-2) in a dosedependent manner, emodin showed anti SARS-CoV activity (Ho, Wu, Chen, Li, & Hsiang, 2007) . In another study conducted by Song et al. in 2018, emodin effectively subsided airway inflammation and activated macrophages in murine asthma model (Song et al., 2018) . Triterpenic acids isolated from jujube aqueous extract have shown inhibitory effects on inflammatory cells such as proliferation of splenocytes stimulated by prostratin and nitric oxide that is produced by macrophages (Yu et al., 2012) . Another study showed a strong protective role of jujube fruits against acute and chronic inflammatory reactions in rats by reducing nitric oxide expression (Goyal, Sharma, & Singh, 2011) . In this study, polysaccharides significantly raised spleen indexes, improved serum hemolysin formation, increased phagocytic activity of macrophages, and inhibited edema in mice (Zou, Chen, Sun-Waterhouse, Zhang, & Li, 2018) . Akbay, Basaran, Undeger, and Basaran (2003) . Nettle extract significantly prevented eosinophilia, leucocytes, and lymphocytes levels in serum and effectively suppressed inflammatory cells in the asthmatic rat model. Also, lipid peroxidation generated by allergen was significantly reduced in lung tissue (Zemmouri et al., 2017) . Gudej, 1990) . Mucilage polysaccharides of marshmallow administered intraperitoneally to mice revealed anti-inflammatory activity by enhancing phagocytic activity of macrophages in the carbon-clearance test (Naqvi, Khan, & Vohora, 1991) . In another study, hypolaetin 8-glucoside (flavonoid in marshmallow) repressed the acute phase of adjuvant carrageenan-induced inflammation, more even than phenylbutazone (Al-Snafi, 2013) . Marshmallow polysaccharides that contain the highest proportion of the uronic acid component, displayed statistically significant cough-repressing activity than non-narcotic drugs applied in clinical practice to treat coughing (Sutovska, Nosalova, Franova, & Kardosova, 2007) . Also, combination of the extracts of Zingiber officinale and A. officinalis diminished severity of acute bronchitis-induced coughs (Roohi Broujeni, Ganji, & Roohi Broujeni, 2009 ). In a double-blind clinical study, the effect of marshmallow on cough associated with angiotensin-converting enzyme F I G U R E 5 Comparison of secondary outcomes including (a) chest pain, (b) cramp, (c) diarrhea, (d) laryngeal pain, and (e) sore throat in two groups on days 0, 3, 7 inhibitors was evaluated. Sixty patients received marshmallow (40 mg, three times daily, for four weeks). The severity of the cough in the group that has been treated by marshmallow had a significant reduction. Eight patients in the marshmallow group demonstrated almost complete cough abolition (Rouhi & Ganji, 2007) .

Treatment strategies for treating COVID-19 patients include corticosteroids, a combination of wide-ranging antiviral medicines, healing plasma, some antibiotics, and supportive care (Jahan & Onay, 2020) . Moreover, lopinavir-ritonavir treatment beyond standard care was not efficient for hospitalized adult patients with severe COVID-19 (Cao et al., 2020) . Also, intravenous remdesivir did not significantly improve mortality, time to clearance of virus, and clinical improvement in patients with serious COVID-19 compared with placebo . Thus, any supplements or treatments that can help alleviate symptoms and enhance tolerance against COVID-19, even using traditional medicinal knowledge seem promising. Medicinal herbs used in this study might not be regarded a complete treatment, but the results show that they can be beneficial for the patients in this critical situation. Open-label design of this study due to the COVID-19 pandemic was main limitation of this study.

The present study demonstrated that these natural decoction and capsules treatment plus routine care significantly decreased duration of hospital stay, accelerate clinical improvement, and alleviated symptoms such as fever, dry cough, anorexia, muscle pain, and runny nose. Ghaderi, and Razieh Eshaghian helping us in this project.

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The authors declare no potential conflict of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0001-5395-819X Samaneh Soleymani https://orcid.org/0000-0002-5084-7870Mohieddin Jafari https://orcid.org/0000-0002-6991-8587Parva Namiranian https://orcid.org/0000-0003-0887-5584Arman Zargaran https://orcid.org/0000-0003-4351-3861