Efficacy and safety of novel herbal tablets in COVID-19 patients in hospital stay days, ICU admission and mortality rate thereof: An open-label, single-blind randomized clinical trial

AUTHORS

Mojtaba Varshochi 1 , Mohammad Shahi 2 , Maryam Rahimzadeh 3 , Hasan Amini ORCID 2 , 4 , 5 , Ramin Mohammadzadeh ORCID 2 , 6 , *

1 Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

3 Department of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran

5 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

6 Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

How to Cite: Varshochi M, Shahi M, Rahimzadeh M, Amini H, Mohammadzadeh R. Efficacy and safety of novel herbal tablets in COVID-19 patients in hospital stay days, ICU admission and mortality rate thereof: An open-label, single-blind randomized clinical trial. Jundishapur J Nat Pharm Prod.In Press(In Press):e117677. doi: 10.5812/jjnpp.117677.

ARTICLE INFORMATION

Jundishapur Journal of Natural Pharmaceutical Products: In Press (In Press); e117677
Published Online: November 13, 2021
Article Type: Research Article
Received: July 6, 2021
Revised: September 20, 2021
Accepted: October 3, 2021
Uncorrected Proof scheduled for 17 (2)
Crossmark
Crossmark
CHECKING
READ FULL TEXT

Abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the super-spreading virus, has claimed hundreds of thousands of lives worldwide.

Objectives: This study aimed to evaluate the effectiveness of the novel suggested herbal compound, formulated as compressed tablets, in reducing the length of hospital stay (LoS), intensive care unit (ICU) admission, and mortality in confirmed COVID-19 cases.

Methods: Following an open-label, single-blind randomized clinical trial design, a total of 200 patients aged 18-65 admitted to Imam Reza hospital in Tabriz, northwest of Iran, were randomized to intervention and control groups in a 1:1 ratio, i.e., 100 subjects in each group. The former received standard treatment along with the compressed herbal tablets, and the latter only received the standard treatment. Adverse reactions incidence within 180 days after the beginning of the intervention was set as the primary safety endpoint. The most important and active ingredients of the tablets were Terminalia chebula, Glycyrrhiza glabra, Anacyclus pyrethrum, Senna alexandrina, Ferrula asafoetida, Pistacia lentiscus, Zizyphus jujuba, Crocus sativus, Echinacea angustifolia, and Hyssopus officinalis. This trial is registered at the Iranian Registry of Clinical Trials (code: IRCT20200522047545N1).

Results: Those in the intervention arm had significantly lower rates of LoS (7.38 vs. 9.45, P = 0.030), ICU admission (6 out of 100 vs. 32 out of 100, P = 0.000), and mortality (1 vs. 19 out of 100, P = 0.000).

Conclusions: Our observations suggest that adequate improvement is provided by the prepared herbal compound along with substantial savings in hospitalization hoteling costs. While further multi-center studies with a larger sample size are needed to extend our knowledge regarding the effect of this new option, these novel clinical data may well provide a new alternative for the management of COVID-19 disease.

1. Background

The new infectious disease triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread broadly and emerged as a complicated illness that can remain asymptomatic or cause modest symptoms such as clusters of acute respiratory illness signs like fever, cough, dyspnea, pneumonia, etc. (1-3). Also, one-fifth of the hospitalized cases develop Acute Respiratory Distress Syndrome (ARDS) and require intensive care unit (ICU) treatments (4). While multiple strategies such as social distancing, self-isolation, and contact tracing might be prospective to achieve control of SARS-CoV-2 transmission, still a growing number of more than 182.3 million people with confirmed diagnoses of and more than 3.9 million deaths from the disease have been currently reported (5-7).

On the other hand, owing to the lack of proven drugs for the treatment of the proceeding coronavirus disease 2019 (COVID-19) pandemic, novel effective formulations of pharmaceuticals are in major attention (8). Fortunately, several groups dedicated themselves to achieving anti-SARS-Cov-2 modalities worldwide, of which herbal compounds and traditional medicine have been widely developed (9-11). These formulations indispensably played a vital role in the prevention and treatment programs for COVID-19 management, especially in China and South Korea, with a combination of modern medicine where they reduced the prevalence of the disease and mortality (9, 12, 13).

Reviewing the literature for formulations of traditional medicine and initial understanding of the COVID-19 disease, the authors formulated a novel herbal compound. Being a simple way for drug delivery and the most desired choice of the patients (14, 15), this formula, which was composed of 18 herb components and is being patented in the Iranian Patent Office (IPO) with an application number of 139950140003008767, was prepared as compressed tablets. The tablets are composed mainly: Terminalia chebula, Glycyrrhiza glabra, Anacyclus pyrethrum, Senna alexandrina, Ferrula asafoetida, Pistacia lentiscus, Zizyphus jujuba, Crocus sativus, Echinacea angustifolia, and Hyssopus officinalis. Moreover, we made use of other additional and complementary herbal derivatives and pharmaceutical excipients according to the traditional and modern medicine principles to make stable and uniform tablets. The herbal ingredients were selected due to their host-directed regulation and certain antiviral effects, which is stated by the available data in the Pharmacognosy science and traditional medicine (16-19).

2. Objectives

The current open-label, single-blind, randomized clinical trial was intended to scrutinize the efficacy and safety of novel oral pharmaceutical tablets with an innovative formulation of herbal ingredients. We sought to test whether the formulation is capable of altering the length of hospital stay (LoS), intensive care unit (ICU) admission, and mortality in patients with a confirmed diagnosis of COVID-19.

3. Methods

3.1. Study Design and Participants

Before starting the study, by referring to the literature and reviewing the available articles and books, the plants used in the management of viral triggered diseases such as severe acute respiratory syndrome (SARS), influenza, COVID-19, etc., especially in China and Korea, were selected and matched to the compounds and native plants of Iran botany and, finally, we presented a new plant composition. The most important and active ingredients of the tablets were Terminalia chebula, Glycyrrhiza glabra, Anacyclus pyrethrum, Senna alexandrina, Ferrula asafoetida, Pistacia lentiscus, Zizyphus jujuba, Crocus sativus, Echinacea angustifolia, and Hyssopus officinalis. Table 1 summarizes the details of the main active ingredients of this herbal compound and the antiviral, anti-inflammatory, and immunomodulatory effects thereof. Due to the warm nature of the composition, using the resources and references of Iranian traditional medicine, supplementary herbal ingredients had been added to the formulation to modify the nature. Also, common pharmaceutical excipients (lubricant, binders, etc.) were utilized in tablets’ composition to make tablets with appropriate physicochemical properties (e.g., hardness, erosion, dissolution rate, and stability).

Table 1. Active ingredients of the herbal compressed tablets and their pharmaceutical effects.
NumberPlant NameAntiviral Effects, (Target Virus)Anti-Inflammatory Effects (Ref.)Immunomodulatory Effects (Ref.)Parts Used for anti-SARS-CoV-2 Effects (Ref.)
1Terminalia chebulaDengue virus (16)(20)(21, 22)Plant extracts (23, 24)
2Glycyrrhiza glabraH1N1 (25, 26)(27, 28)(29-31)Root (32)
HCV (33)
HSV-1 (34)
3Anacyclus pyrethrumCommon cold (35)(36)(37, 38)Root (39, 40)
4Senna alexandrinaHSV-1 (41)(42)(43-45)Leaf (46)
5Ferrula asafoetidaHSV-1 (47)(48, 49)(50, 51)Root, Leaf (52)
6Pistacia lentiscusHSV1 (53, 54)(55, 56)(57, 58)Root, Stem, Leaf (59)
HSV-2 (60)
7Zizyphus jujubaInfluenza A (61)(62, 63)(64, 65)Fruit (66, 67)
8Crocus sativusHPV (68)(69, 70)(69)Stigma, Style (67, 71)
9Echinacea angustifoliaCommon cold (72)(73)(74)Root, Stem, Leaf (75)
10Hyssopus officinalisHIV (76)(77)(78)Dry weight of aerial parts (79)

This randomized, open-label, single-blind, superiority clinical trial was done at Imam Reza (PBUH) hospital in Tabriz, northwest of Iran. Two hundred COVID-19 patients aged 18-65 years with tendency to attend a clinical trial study signed the informed consent and were randomized to either the treatment group (standard treatment based on the Iranian national COVID-19 treatment protocol (i.e., Remdesivir, Favipiravir, Hydroxychloroquine, and supportive oxygen treatment) along with the compressed herbal tablets) or the control group (only received the standard treatment) in a 1:1 ratio, i.e., 100 subjects in each arm. Usage of all other common medications, such as corticosteroids, bronchodilators, etc., was almost the same in both groups. The incidence of the adverse reactions within 180 days after the beginning of the intervention was set as the safety endpoint, and a deliberate delay for 180 days in reporting the results was set to monitor the last patients for possible adverse effects.

The inclusion criteria were being aged 18 to 65 years, positive PCR or CT scan findings based on COVID-19 disease, willingness to participate in a clinical trial study, and disease severity in the mild to the moderate range with the following symptoms: low-grade fever (around 37.7 degrees Celsius), dry cough, fatigue, headache, new loss of taste or smell, gastrointestinal upset, including vomiting and diarrhea and/or itchy, painful patches on the skin.

The key exclusion criteria were namely severe COVID-19 disease status, liver or kidney failure, organ transplantation experience, pregnancy or breastfeeding, and, finally, receiving any clinical trial medication in the last 30 days before the enrolment.

3.2. The Extraction Method and Standardization of the Formula

The composition of the plants, after grinding into a fine powder, was formulated in the form of compressed oral tablets following standard pharmaceutical methods, including mixing the dry raw herbal components, granulation, wet screening using a sieve with 12 mesh size, drying in the oven in 400C, dry screening using a sieve with 18 mesh size, glidant to improve its flowability and lubricant to reduce friction between surfaces in mutual contact, final mixing in the Turbula Mixer for 30 minutes and the compression as a final point. Preliminary phytochemical tests and heavy metal analysis were performed according to standard methods (80).

3.3. Sample Size Determination

The minimum sample size was estimated as 200 subjects (100 cases in each group) using the Cochran formula and by considering previous similar studies.

3.4. Randomization and Masking

Referring to the http://randomizer.org URL and selecting Generate numbers item, 200 numbers in the range of 1000 to 100000 were created for the list of patients. Then, the odd and even numbers were designated as the treatment group and control group, respectively. Patients were masked to treatment allocation due to their isolated hospital rooms, but the administrators and nurses were aware of the orders.

3.5. Procedures

The prepared innovative formulation was administered orally to the patients in the treatment group 3 times a day for at least 7 days (3 tablets in each turn) and directly observed by the investigator. Also, the patients enrolled in the trial were subjected to a wide range of tests, including complete blood count (CBC) and serum AST/ALT levels in the admission state and a final stage of the discharge process. All blood samples taken from patients were sent to the hospital laboratory (Biochemistry laboratory of Imam Reza (PBUH) Hospital) for CBC and serum ALT/AST measurements. We kept in contact with the patients who were discharged from the hospital in less than 7 days to make sure that the study protocol was precisely being fulfilled (Figure 1). Patients requiring or likely to require advanced respirational support alone, or together with more organ systems, hemodynamic instability necessitating vasopressors, and oxygen saturations less than 85% were set as ICU admission criteria. Acute physiology and chronic health evaluation (APACHE) score for all patients in each arm was calculated.

Figure 1. Study design. The experimental study steps used in the two study groups have been summarized

3.6. Outcomes

The main outcomes included reduced length of hospitalization stay (LoS) due to improved symptoms in a lesser time, lower need for intensive care unit (ICU) admission, and decreased mortality.

3.7. Statistical Analysis

We have reported the quantitative and qualitative variables by way of mean ± standard deviation and percentage (%), respectively. The normality and non-normality of the distributions of the variables were respectively compared between the groups by means of the Independent Sample t-test and Mann-Whitney. Only the observed outcomes were used for data analysis. Statistical significance was based upon an alpha error probability of 5% (P < 0.05 was considered significant) and power of 80%. Variables were summarized with two-way repeated measure ANOVA with comparisons within and between-group effects. Analysis of variance was used to assess the effects of treatment interventions on the key outcomes in the current study. Data analysis was administered using SPSS version 26. The research purpose and methodology were subjected to scrutiny by the Research Ethics Committees of Tabriz University of Medical Sciences (code: ID of IR.TBZMED.REC.1399.126). In addition, this trial is registered at the Iranian Registry of Clinical Trials (code: IRCT20200522047545N1).

3.8. Role of the Funding Source

The funder had no role in the design of the study or data interpretation. The corresponding author had final responsibility for the study and full access to all the data, as well as final responsibility for the decision to submit for publication.

4. Results

From July 26, 2020, to September 26, 2020, we screened 250 individuals, of which 200 participants with similar demographic and disease characteristics were enrolled in this randomized clinical trial. Fifty patients (i.e., 32 did not meet the inclusion/exclusion criteria, and 18 refused to participate) were excluded. All eligible patients were randomly allocated to either the treatment group (who received the standard treatment along with the compressed herbal tablets) or the control group (who only received the standard treatment) in a 1:1 ratio, i.e., 100 cases in each arm. Of whom, 200 (100%) completed the trial either in the hospitalization period for patients with LoS ≥ 7 days or after discharge from the hospital for individuals with LoS < 7 days.

Although the randomization and masking were done using the standard procedure mentioned in the Methods, due to the special conditions and pandemic emergencies, older people were in the standard. But regarding that older cases are at higher risk of death due to Covid-19, this limitation was not effective to the results of the study.

Adverse reactions incidence within 180 days after the beginning of the intervention was set as the safety endpoint. Therefore, we made a deliberate delay for 180 days in reporting the results due to monitoring patients who were enrolled in the study in the latest week of the trial procedure for possible adverse effects (Figure 2). Baseline demographic characteristics of the participants in the standard group were similar among the treatment groups in terms of gender and mean age (Table 2). The number of patients in different age groups is also reported in Figure 3. The body mass index (BMI) and APACHE score in both groups were almost equal (9.8 ± 1.2 for the standard group vs. 9.5 ± 3.6 for the treatment group).

Table 2. Baseline Demographic Characteristics of the Participants in the Standard vs. Treatment Groups
VariableFrequency (%)NumberTreatment GroupStandard Group
Sex
Female48964749
Male521045351
Total100200100100
Age (range)
18-252.50514
26-359.5019910
36-4518362412
46-5519.50392514
56-6018361719
61-6532.50652441
Total100200100100
Figure 2. CONSORT diagram-trial profile. *Three patients were pregnant. 9 patients had kidney transplantation experience. 8 patients had History of malignancies. 12 received clinical trial medication in the last 30 days
Figure 3. Number of patients in different age groups

Notably, patients treated within the treatment arm represented significant reductions in LoS (7.38 vs. 9.45, P = 0.030), ICU admission (6 out of 100 vs. 32 out of 100, P = 0.000), and mortality (1 vs. 19 out of 39, P = 0.000) (Table 2). The incidence of drug interactions within the study period was monitored by Prof. Varshochi and the nursing office of the hospital, and there were none to be declared. Although there were some complications of mild hyperthermia in leg toes (5 participants, without a rise in the whole-body temperature or fever status), no other minor/major adverse events were found or reported in the patients of this study.

The cases related to the above findings are reported separately in Tables 3 and 4. According to the baseline laboratory data as well the follow-up laboratory results, during the trial period, which lasted more than 180 days, there were no specific complaints from patients about drug side effects, and laboratory findings did not have any specific case of side effects and adverse effects on patients' body function. The CBC and ALT/AST values also remained unchanged. The values for CBC and ALT/AST are reported in Table 5.

Table 3. Number of Length of Hospital Stay Days (LoS)
Hospitalization DaysFrequency in Treatment GroupFrequency in Standard Group
210
3163
4427
51419
61314
7911
873
975
1032
1132
1212
1311
1412
1532
1632
1711
1801
1920
2021
2230
2310
2510
2810
3501
3711
4020
Table 4. Mortality Rate, ICU Admission a
Treatment GroupStandard GroupTotalP Value
Fate0
Alive9981180
Dead11920
ICU admission, Number632380

a Statistical significance was based upon an alpha error probability of 5% (P < 0.05 was considered significant) and a power for 80%. Variables were summarized with two-way repeated measure ANOVA with comparisons within and between-group effects.

Table 5. CBC and Serum ALT/AST Measurements Before and After Intervention in the Treatment Group a
VariableNumberBefore intervention, (Mean)After intervention, (Mean)P Value
WBC (per mm3)2006553.66789.70.98
Lymphocyte (per mm3)195 b2465.12998.31
LDH (U/L)157 b575.8617.20.88
RBC (mm3)2005.455.420.36
Hemoglobin (g/dL)189 b13.914.90.46
Platelet (mm3)200255.2219.40.05
AST (U/L)191 b29.932.40.57
ALT (U/L)191 b21.625.10.66
ESR (mm/hb)20041.238.10.33

a Statistical significance was based upon an alpha error probability of 5% (P < 0.05 was considered significant) and a power for 80%. Variables were summarized with two-way repeated measure ANOVA with comparisons within and between-group effects.

b In some patients, the test was not ordered at admission or after intervention.

With the onset of COVID-19 disease in late 2019, many researchers around the world have constantly tried to find an effective treatment for the disease. However, to date, these efforts have not led to a definitive drug or treatment (8). This study was designed to evaluate the efficacy and safety of a new herbal compound formulated as compressed tablets for COVID-19 patients. The results indicated significant declines in LoS (7.38 vs. 9.45, P = 0.030), ICU admissions (6 out of 100 vs. 32 out of 100, P = 0.000), and mortality (1 vs. 19 out of 100, P = 0.000) among subjects in the intervention group.

Compressed tablets contained multi-ingredient compositions, including mainly Terminalia chebula, Glycyrrhiza glabra, Anacyclus pyrethrum, Senna alexandrina, Ferrula asafoetida, Pistacia lentiscus, Zizyphus jujuba, Crocus sativus, Echinacea angustifolia, and Hyssopus officinalis, which have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects, and other additional and complementary herbal derivative and pharmaceutical excipients according to the Iranian traditional medicine and modern pharmaceutical principles to make stable and uniform tablets (Table 1). Several other groups dedicated themselves to achieving anti-SARS-Cov2 modalities worldwide, of which herbal compounds and traditional medicine have been widely developed (9-11), and their results, fortunately, played a vital role in the prevention and treatment programs developed for COVID-19 management, especially in China and South Korea, which according to the evidence, they could successfully reduce the prevalence and the mortality caused by of the disease (9, 12, 13).

In our study, we observed 21.9%, 26%, and 18% improvements in LoS (7.38 vs. 9.45, P = 0.030), ICU admission (6 out of 100 vs. 32 out of 100, P = 0.000), and mortality (1 vs. 19 out of 100, P = 0.000), respectively, in the treatment group. Individuals in the treatment group received standard treatment based on the Iranian national COVID-19 treatment protocol (Remdesivir, Favipiravir, Hydroxychloroquine, and supportive oxygen treatment) along with the herbal compressed tablets as an intervention (Tables 3 and 4). The results of the study have been confirmed by the Committee for Ethics in Biomedical Research, Tabriz University of Medical Sciences, Iran.

5. Discussion

Given the promising results of this randomized clinical trial, the innovative formulation of herbal tablets can provide a glimmering light in the darkness of the COVID-19 pandemic to manage and overcome the disease. Reduced mortality, lower duration of hospitalization, and non-admission to the intensive care unit indicate the effectiveness of herbal compressed tablets. We believe that the special properties of the medicine (e.g., the overall host-directed regulation and certain antiviral, anti-inflammatory, strengthening, and supportive effects on patients’ immune system) will possibly be the promising mechanism of action thereof. Although due to trial limitations, potential bias, imprecision, etc. a larger study with more participants can better confirm the results of this clinical trial, verifying that the usage of the introduced tablets may plausibly facilitate the eradication of intimidating and catastrophic COVID-19 disease.

Footnotes

References

  • 1.

    Ansarin K, Tolouian R, Ardalan M, Taghizadieh A, Varshochi M, Teimouri S, et al. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial. Bioimpacts. 2020;10(4):209-15. eng. doi: 10.34172/bi.2020.27. [PubMed: 32983936]. [PubMed Central: PMC7502909].

  • 2.

    Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, et al. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020;203:105751. eng. doi: 10.1016/j.jsbmb.2020.105751. [PubMed: 32871238]. [PubMed Central: PMC7456194].

  • 3.

    Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141-54. eng. doi: 10.1038/s41579-020-00459-7. [PubMed: 33024307]. [PubMed Central: PMC7537588].

  • 4.

    Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. eng. doi: 10.1016/s0140-6736(20)30211-7. [PubMed: 32007143]. [PubMed Central: PMC7135076].

  • 5.

    World Health Organization. World Health Organization coronavirus disease (COVID-19) dashboard. 2020, [cited November 23, 2020]. Available from: https://covid19.who.int/.

  • 6.

    Kucharski AJ, Klepac P, Conlan AJK, Kissler SM, Tang ML, Fry H, et al. Effectiveness of isolation, testing, contact tracing, and physical distancing on reducing transmission of SARS-CoV-2 in different settings: a mathematical modelling study. Lancet Infect Dis. 2020;20(10):1151-60. eng. doi: 10.1016/s1473-3099(20)30457-6. [PubMed: 32559451]. [PubMed Central: PMC7511527].

  • 7.

    Reddy KP, Shebl FM, Foote JHA, Harling G, Scott JA, Panella C, et al. Cost-effectiveness of public health strategies for COVID-19 epidemic control in South Africa: a microsimulation modelling study. Lancet Glob Health. 2021;9(2):e120-9. eng. doi: 10.1016/s2214-109x(20)30452-6. [PubMed: 33188729]. [PubMed Central: PMC7834260].

  • 8.

    Vijayvargiya P, Garrigos ZE, Almeida NEC, Gurram PR, Stevens RW, Razonable RR. Treatment considerations for COVID-19: a critical review of the evidence (or lack thereof). Mayo Clin Proc. Elsevier; 2020. p. 1454-66.

  • 9.

    Luo H, Tang QL, Shang YX, Liang SB, Yang M, Robinson N, et al. Can Chinese Medicine Be Used for Prevention of Corona Virus Disease 2019 (COVID-19)? A Review of Historical Classics, Research Evidence and Current Prevention Programs. Chin J Integr Med. 2020;26(4):243-50. eng. doi: 10.1007/s11655-020-3192-6. [PubMed: 32065348]. [PubMed Central: PMC7088641].

  • 10.

    Ang L, Lee HW, Choi JY, Zhang J, Soo Lee M. Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines. Integr Med Res. 2020;9(2):100407. eng. doi: 10.1016/j.imr.2020.100407. [PubMed: 32289016]. [PubMed Central: PMC7104236].

  • 11.

    Zhang DH, Wu KL, Zhang X, Deng SQ, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med. 2020;18(2):152-8. eng. doi: 10.1016/j.joim.2020.02.005. [PubMed: 32113846]. [PubMed Central: PMC7102521].

  • 12.

    Ni L, Chen L, Huang X, Han C, Xu J, Zhang H, et al. Combating COVID-19 with integrated traditional Chinese and Western medicine in China. Acta Pharm Sin B. 2020;10(7):1149-62. eng. doi: 10.1016/j.apsb.2020.06.009. [PubMed: 32834946]. [PubMed Central: PMC7319939].

  • 13.

    Chen X, Wu Y, Chen C, Gu Y, Zhu C, Wang S, et al. Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening. Acta Pharm Sin B. 2021;11(1):222-36. eng. doi: 10.1016/j.apsb.2020.10.002. [PubMed: 33072499]. [PubMed Central: PMC7547831].

  • 14.

    Patel MR, Patel RB, Thakore SD. Nanoemulsion in drug delivery. Applications of nanocomposite materials in drug delivery. Elsevier; 2018. p. 667-700.

  • 15.

    Mohammadzadeh R, Baradaran B, Yousefi B, Valizadeh H, Zakeri-Milani P. Attenuation of intestinal efflux pump thru polymers and preservatives. J Res Pharm. 2019;23(4):632-41.

  • 16.

    Lin LT, Hsu WC, Lin CC. Antiviral natural products and herbal medicines. J Tradit Complement Med. 2014;4(1):24-35. eng. doi: 10.4103/2225-4110.124335. [PubMed: 24872930]. [PubMed Central: PMC4032839].

  • 17.

    Bakhtiar L, Nasr SH. Canon of Medicine 5 Volume Set. Kazi Publications, Incorporated; 2014.

  • 18.

    Heber D. PDR for herbal medicines. Thomson PDR; 2004.

  • 19.

    Evans WC. Trease and Evans Pharmacognosy. Toronto: Saunders; 2002.

  • 20.

    Jami MSI, Sultana Z, Ali ME, Begum MM, Haque MM. Evaluation of analgesic and anti-inflammatory activities on ethanolic extract of Terminalia chebula fruits in experimental animal models. Am J Plant Sci. 2014;5:63-9.

  • 21.

    Belapurkar P, Goyal P, Tiwari-Barua P. Immunomodulatory effects of triphala and its individual constituents: a review. Indian J Pharm Sci. 2014;76(6):467-75. eng. [PubMed: 25593379]. [PubMed Central: PMC4293677].

  • 22.

    Shivaprasad HN, Kharya MD, Rana AC, Mohan S. Preliminary Immunomodulatory Activities of the Aqueous Extract of Terminalia chebula. Pharm Biol. 2006;44(1):32-4.

  • 23.

    Upadhyay S, Tripathi PK, Singh M, Raghavendhar S, Bhardwaj M, Patel AK. Evaluation of medicinal herbs as a potential therapeutic option against SARS-CoV-2 targeting its main protease. Phytother Res. 2020;34(12):3411-9. eng. doi: 10.1002/ptr.6802. [PubMed: 32748969]. [PubMed Central: PMC7436756].

  • 24.

    Sharma R, Prajapati GK, Akhoury G. Pentagalloylglucose, a phytochemical from Terminalia chebula can efficiently prevent SARS-CoV-2 entry: In Silico study. Isr J Plant Sci. 2021;1(aop):1-9.

  • 25.

    Baltina LA, Zarubaev VV, Baltina LA, Orshanskaya IA, Fairushina AI, Kiselev OI, et al. Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors. Bioorg Med Chem Lett. 2015;25(8):1742-6. eng. doi: 10.1016/j.bmcl.2015.02.074. [PubMed: 25801933]. [PubMed Central: PMC7127794].

  • 26.

    Wolkerstorfer A, Kurz H, Bachhofner N, Szolar OH. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res. 2009;83(2):171-8. eng. doi: 10.1016/j.antiviral.2009.04.012. [PubMed: 19416738]. [PubMed Central: PMC7126985].

  • 27.

    Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm Biol. 2017;55(1):5-18. eng. doi: 10.1080/13880209.2016.1225775. [PubMed: 27650551]. [PubMed Central: PMC7012004].

  • 28.

    Frattaruolo L, Carullo G, Brindisi M, Mazzotta S, Bellissimo L, Rago V, et al. Antioxidant and Anti-Inflammatory Activities of Flavanones from Glycyrrhiza glabra L. (licorice) Leaf Phytocomplexes: Identification of Licoflavanone as a Modulator of NF-kB/MAPK Pathway. Antioxidants (Basel). 2019;8(6). eng. doi: 10.3390/antiox8060186. [PubMed: 31226797]. [PubMed Central: PMC6616548].

  • 29.

    Ayeka PA, Bian Y, Githaiga PM, Zhao Y. The immunomodulatory activities of licorice polysaccharides (Glycyrrhiza uralensis Fisch.) in CT 26 tumor-bearing mice. BMC Complement Altern Med. 2017;17(1):536. eng. doi: 10.1186/s12906-017-2030-7. [PubMed: 29246138]. [PubMed Central: PMC5732493].

  • 30.

    Mazumder PM, Pattnayak S, Parvani H, Sasmal D, Rathinavelusamy P. Evaluation of immunomodulatory activity of Glycyrhiza glabra L roots in combination with zing. Asian Pac J Trop Biomed. 2012;2(1):S15-20.

  • 31.

    Abtahifroushani SM, EsmaeiliGouvarchinGhaleh H, Rezapor R, MansoriMotlagh B, Rostaei A. Immunomodulatory Effects by Hydroalcoholic Liquorice Root Extracts. J Adv Med Biomed Res. 2014;22(95):112-21.

  • 32.

    Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045-6. eng. doi: 10.1016/s0140-6736(03)13615-x. [PubMed: 12814717]. [PubMed Central: PMC7112442].

  • 33.

    Ashfaq UA, Masoud MS, Nawaz Z, Riazuddin S. Glycyrrhizin as antiviral agent against Hepatitis C Virus. J Transl Med. 2011;9:112. eng. doi: 10.1186/1479-5876-9-112. [PubMed: 21762538]. [PubMed Central: PMC3169469].

  • 34.

    Sabouri Ghannad M, Mohammadi A, Safiallahy S, Faradmal J, Azizi M, Ahmadvand Z. The Effect of Aqueous Extract of Glycyrrhiza glabra on Herpes Simplex Virus 1. Jundishapur J Microbiol. 2014;7(7). eng. e11616. doi: 10.5812/jjm.11616. [PubMed: 25368801]. [PubMed Central: PMC4216581].

  • 35.

    Mouhajir F, Hudson JB, Rejdali M, Towers GHN. Multiple antiviral activities of endemic medicinal plants used by Berber peoples of Morocco. Pharm Biol. 2001;39(5):364-74.

  • 36.

    Jawhari FZ, El Moussaoui A, Bourhia M, Imtara H, Mechchate H, Es-Safi I, et al. Anacyclus pyrethrum (L): Chemical Composition, Analgesic, Anti-Inflammatory, and Wound Healing Properties. Molecules. 2020;25(22). eng. doi: 10.3390/molecules25225469. [PubMed: 33238392]. [PubMed Central: PMC7700217].

  • 37.

    Sharma V, Thakur M, Chauhan NS, Dixit VK. Immunomodulatory activity of petroleum ether extract of Anacyclus pyrethrum. Pharm Biol. 2010;48(11):1247-54. eng. doi: 10.3109/13880201003730642. [PubMed: 20843161].

  • 38.

    Manouze H, Bouchatta O, Gadhi AC, Bennis M, Sokar Z, Ba-M'hamed S. Anti-inflammatory, Antinociceptive, and Antioxidant Activities of Methanol and Aqueous Extracts of Anacyclus pyrethrum Roots. Front Pharmacol. 2017;8:598. eng. doi: 10.3389/fphar.2017.00598. [PubMed: 28928658]. [PubMed Central: PMC5591861].

  • 39.

    Vincent S, Arokiyaraj S, Saravanan M, Dhanraj M. Molecular Docking Studies on the Anti-viral Effects of Compounds From Kabasura Kudineer on SARS-CoV-2 3CL(pro). Front Mol Biosci. 2020;7:613401. eng. doi: 10.3389/fmolb.2020.613401. [PubMed: 33425994]. [PubMed Central: PMC7785853].

  • 40.

    Prasad A, Muthamilarasan M, Prasad M. Synergistic antiviral effects against SARS-CoV-2 by plant-based molecules. Plant Cell Rep. 2020;39(9):1109-14. eng. doi: 10.1007/s00299-020-02560-w. [PubMed: 32561979]. [PubMed Central: PMC7303273].

  • 41.

    Silva O, Barbosa S, Diniz A, Valdeira ML, Gomes E. Plant extracts antiviral activity against Herpes simplex virus type 1 and African swine fever virus. Int J Pharmacogn. 1997;35(1):12-6.

  • 42.

    Guarize L, Costa JC, Dutra LB, Mendes RF, Lima IV, Scio E. Anti-inflammatory, laxative and intestinal motility effects of Senna macranthera leaves. Nat Prod Res. 2012;26(4):331-43. eng. doi: 10.1080/14786411003754264. [PubMed: 21432718].

  • 43.

    Farid A, Kamel D, Abdelwahab Montaser S, Mohamed Ahmed M, El Amir M, El Amir A. Synergetic role of senna and fennel extracts as antioxidant, anti-inflammatory and anti-mutagenic agents in irradiated human blood lymphocyte cultures. J Radiat Res Appl Sci. 2020;13(1):191-9.

  • 44.

    Zhang WJ, Wang S, Kang CZ, Lv CG, Zhou L, Huang LQ, et al. Pharmacodynamic material basis of traditional Chinese medicine based on biomacromolecules: a review. Plant Methods. 2020;16:26. eng. doi: 10.1186/s13007-020-00571-y. [PubMed: 32140174]. [PubMed Central: PMC7049221].

  • 45.

    Balaban YH, Aka C, Koca-Caliskan U. Liver immunology and herbal treatment. World J Hepatol. 2017;9(17):757-70. eng. doi: 10.4254/wjh.v9.i17.757. [PubMed: 28660010]. [PubMed Central: PMC5474722].

  • 46.

    Kumar S, Naeem R, Radhawi AST, Mahmood SU, Batool Z, Naqi SRA. Senna Makki and the COVID-19 pandemic: a reflection from Pakistan. Int J Community Med Public Health. 2020;7(12):5194.

  • 47.

    Ghannadi A, Fattahian K, Shokoohinia Y, Behbahani M, Shahnoush A. Anti-Viral Evaluation of Sesquiterpene Coumarins from Ferula assa-foetida against HSV-1. Iran J Pharm Res. 2014;13(2):523-30. eng. [PubMed: 25237347]. [PubMed Central: PMC4157027].

  • 48.

    Bagheri SM, Hedesh ST, Mirjalili A, Dashti R. Evaluation of Anti-inflammatory and Some Possible Mechanisms of Antinociceptive Effect of Ferula assa foetida Oleo Gum Resin. J Evid Based Complementary Altern Med. 2016;21(4):271-6. eng. doi: 10.1177/2156587215605903. [PubMed: 26427790].

  • 49.

    Bagheri SM, Dashti R, Morshedi A. Antinociceptive effect of Ferula assa-foetida oleo-gum-resin in mice. Res Pharm Sci. 2014;9(3):207-12. eng. [PubMed: 25657791]. [PubMed Central: PMC4311286].

  • 50.

    Amalraj A, Gopi S. Biological activities and medicinal properties of Asafoetida: A review. J Tradit Complement Med. 2017;7(3):347-59. eng. doi: 10.1016/j.jtcme.2016.11.004. [PubMed: 28725631]. [PubMed Central: PMC5506628].

  • 51.

    Safari O, Sarkheil M, Paolucci M. Dietary administration of ferula (Ferula asafoetida) powder as a feed additive in diet of koi carp, Cyprinus carpio koi: effects on hemato-immunological parameters, mucosal antibacterial activity, digestive enzymes, and growth performance. Fish Physiol Biochem. 2019;45(4):1277-88. eng. doi: 10.1007/s10695-019-00674-x. [PubMed: 31256305].

  • 52.

    Natesh J, Mondal P, Penta D, Abdul Salam AA, Meeran SM. Culinary spice bioactives as potential therapeutics against SARS-CoV-2: Computational investigation. Comput Biol Med. 2021;128:104102. eng. doi: 10.1016/j.compbiomed.2020.104102. [PubMed: 33190011]. [PubMed Central: PMC7606080].

  • 53.

    Jin F, Ma K, Chen M, Zou M, Wu Y, Li F, et al. Pentagalloylglucose Blocks the Nuclear Transport and the Process of Nucleocapsid Egress to Inhibit HSV-1 Infection. Jpn J Infect Dis. 2016;69(2):135-42. eng. doi: 10.7883/yoken.JJID.2015.137. [PubMed: 26166506].

  • 54.

    Pei Y, Chen ZP, Ju HQ, Komatsu M, Ji YH, Liu G, et al. Autophagy is involved in anti-viral activity of pentagalloylglucose (PGG) against Herpes simplex virus type 1 infection in vitro. Biochem Biophys Res Commun. 2011;405(2):186-91. eng. doi: 10.1016/j.bbrc.2011.01.006. [PubMed: 21216235].

  • 55.

    Maxia A, Sanna C, Frau MA, Piras A, Karchuli MS, Kasture V. Anti-inflammatory activity of Pistacia lentiscus essential oil: involvement of IL-6 and TNF-alpha. Nat Prod Commun. 2011;6(10):1543-4. eng. [PubMed: 22164803].

  • 56.

    Dellai A, Souissi H, Borgi W, Bouraoui A, Chouchane N. Antiinflammatory and antiulcerogenic activities of Pistacia lentiscus L. leaves extracts. Ind Crops Prod. 2013;49:879-82.

  • 57.

    Kottakis F, Kouzi-Koliakou K, Pendas S, Kountouras J, Choli-Papadopoulou T. Effects of mastic gum Pistacia lentiscus var. Chia on innate cellular immune effectors. Eur J Gastroenterol Hepatol. 2009;21(2):143-9. eng. doi: 10.1097/MEG.0b013e32831c50c9. [PubMed: 19212203].

  • 58.

    Gacem MA, El Hadj-Khelil AO, Boudjemaa B, Gacem H. Phytochemistry, Toxicity and Pharmacology of Pistacia lentiscus, Artemisia herba-alba and Citrullus colocynthis. Sustain Agr Rev. 2020;39:57-93.

  • 59.

    Shiri AH, Rayatdoost E, Afkhami H, Ravanshad R, Hosseini SE, Kalani N, et al. The herbal combination of Sugarcane, Black Myrobalan, and mastic as a supplementary treatment for COVID-19: a randomized clinical trial. medRxiv. 2021.

  • 60.

    Benzekri R, Limam F, Bouslama L. Combination effect of three anti-HSV-2 active plant extracts exhibiting different modes of action. Orient Pharm Exp Med. 2020;20(2):223-31.

  • 61.

    Hong EH, Song JH, Kang KB, Sung SH, Ko HJ, Yang H. Anti-Influenza Activity of Betulinic Acid from Zizyphus jujuba on Influenza A/PR/8 Virus. Biomol Ther (Seoul). 2015;23(4):345-9. eng. doi: 10.4062/biomolther.2015.019. [PubMed: 26157551]. [PubMed Central: PMC4489829].

  • 62.

    Al-Reza SM, Yoon JI, Kim HJ, Kim JS, Kang SC. Anti-inflammatory activity of seed essential oil from Zizyphus jujuba. Food Chem Toxicol. 2010;48(2):639-43. eng. doi: 10.1016/j.fct.2009.11.045. [PubMed: 19944733].

  • 63.

    Mesaik AM, Poh HW, Bin OY, Elawad I, Alsayed B. In Vivo Anti-Inflammatory, Anti-Bacterial and Anti-Diarrhoeal Activity of Ziziphus Jujuba Fruit Extract. Open Access Maced J Med Sci. 2018;6(5):757-66. eng. doi: 10.3889/oamjms.2018.168. [PubMed: 29875842]. [PubMed Central: PMC5985874].

  • 64.

    Yu ZP, Xu DD, Lu LF, Zheng XD, Chen W. Immunomodulatory effect of a formula developed from American ginseng and Chinese jujube extracts in mice. J Zhejiang Univ Sci B. 2016;17(2):147-57. eng. doi: 10.1631/jzus.B1500170. [PubMed: 26834015]. [PubMed Central: PMC4757584].

  • 65.

    Ji X, Liu F, Ullah N, Wang M. Isolation, purification, and antioxidant activities of polysaccharides from Ziziphus Jujuba cv. Muzao. Int J Food Prop. 2018;21(1):1-11.

  • 66.

    Verma S, Twilley D, Esmear T, Oosthuizen CB, Reid AM, Nel M, et al. Anti-SARS-CoV Natural Products With the Potential to Inhibit SARS-CoV-2 (COVID-19). Front Pharmacol. 2020;11:561334. eng. doi: 10.3389/fphar.2020.561334. [PubMed: 33101023]. [PubMed Central: PMC7546787].

  • 67.

    Bahramsoltani R, Rahimi R. An Evaluation of Traditional Persian Medicine for the Management of SARS-CoV-2. Front Pharmacol. 2020;11:571434. eng. doi: 10.3389/fphar.2020.571434. [PubMed: 33324206]. [PubMed Central: PMC7724033].

  • 68.

    Khavari A, Bolhassani A, Alizadeh F, Bathaie SZ, Balaram P, Agi E, et al. Chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine generates different anti-tumor effects against tumors expressing the E7 protein of human papillomavirus. Arch Virol. 2015;160(2):499-508. eng. doi: 10.1007/s00705-014-2250-9. [PubMed: 25395243].

  • 69.

    Zeinali M, Zirak MR, Rezaee SA, Karimi G, Hosseinzadeh H. Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review. Iran J Basic Med Sci. 2019;22(4):334-44. eng. doi: 10.22038/ijbms.2019.34365.8158. [PubMed: 31223464]. [PubMed Central: PMC6535192].

  • 70.

    Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol. 2002;2:7. eng. doi: 10.1186/1471-2210-2-7. [PubMed: 11914135]. [PubMed Central: PMC101384].

  • 71.

    Husaini AM, Jan KN, Wani GA. Saffron: A potential drug-supplement for severe acute respiratory syndrome coronavirus (COVID) management. Heliyon. 2021;7(5). eng. e07068. doi: 10.1016/j.heliyon.2021.e07068. [PubMed: 34007917]. [PubMed Central: PMC8118646].

  • 72.

    Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi JD. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med. 2005;353(4):341-8. eng. doi: 10.1056/NEJMoa044441. [PubMed: 16049208].

  • 73.

    Tragni E, Galli CL, Tubaro A, Del Negro P, Della Loggia R. Anti-inflammatory activity of Echinacea angustifolia fractions separated on the basis of molecular weight. Pharmacol Res Commun. 1988;20 Suppl 5:87-90. eng. doi: 10.1016/s0031-6989(88)80848-8. [PubMed: 3247359].

  • 74.

    Catanzaro M, Corsini E, Rosini M, Racchi M, Lanni C. Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea. Molecules. 2018;23(11). eng. doi: 10.3390/molecules23112778. [PubMed: 30373170]. [PubMed Central: PMC6278270].

  • 75.

    Bajrai LH, El-Kafrawy SA, Alnahas RS, Azhar EI. In vitro screening of anti-viral and virucidal effects against SARS-CoV-2 by Hypericum perforatum and Echinacea. bioRxiv. 2021.

  • 76.

    Kreis W, Kaplan MH, Freeman J, Sun DK, Sarin PS. Inhibition of HIV replication by Hyssop officinalis extracts. Antiviral Res. 1990;14(6):323-37. eng. doi: 10.1016/0166-3542(90)90051-8. [PubMed: 1708226].

  • 77.

    Wang HY, Ding JB, Halmurat U, Hou M, Xue ZQ, Zhu M, et al. The effect of Uygur medicine Hyssopus officinalis L on expression of T-bet, GATA-3 and STAT-3 mRNA in lung tissue of asthma rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2011;27(8):876-9.

  • 78.

    Soleimani H, Barzegar M, Sahari MA, Naghdi Badi H. An investigation on the antioxidant activities of Hyssopus officinalis L. and Echinacea purpurea L. plant extracts in oil model system. J Med Plants. 2011;10(37):61-72.

  • 79.

    Babich O, Sukhikh S, Prosekov A, Asyakina L, Ivanova S. Medicinal Plants to Strengthen Immunity during a Pandemic. Pharmaceuticals (Basel). 2020;13(10). eng. doi: 10.3390/ph13100313. [PubMed: 33076514]. [PubMed Central: PMC7602650].

  • 80.

    WHO. Quality control methods of medicinal plant material. Geneva; 1998. 24 p.

  • Copyright © 2021, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
    COMMENTS

    LEAVE A COMMENT HERE: