key: cord-1033832-nj8uxg1t
authors: Panossian, Alexander; Brendler, Thomas
title: The Role of Adaptogens in Prophylaxis and Treatment of Viral Respiratory Infections
date: 2020-09-08
journal: Pharmaceuticals (Basel)
DOI: 10.3390/ph13090236
sha: e83215d5161a993b2a697c4230dac937bcc081d1
doc_id: 1033832
cord_uid: nj8uxg1t

The aim of our review is to demonstrate the potential of herbal preparations, specifically adaptogens for prevention and treatment of respiratory infections, as well as convalescence, specifically through supporting a challenged immune system, increasing resistance to viral infection, inhibiting severe inflammatory progression, and driving effective recovery. The evidence from pre-clinical and clinical studies with Andrographis paniculata, Eleutherococcus senticosus, Glycyrrhiza spp., Panax spp., Rhodiola rosea, Schisandra chinensis, Withania somnifera, their combination products and melatonin suggests that adaptogens can be useful in prophylaxis and treatment of viral infections at all stages of progression of inflammation as well as in aiding recovery of the organism by (i) modulating innate and adaptive immunity, (ii) anti-inflammatory activity, (iii) detoxification and repair of oxidative stress-induced damage in compromised cells, (iv) direct antiviral effects of inhibiting viral docking or replication, and (v) improving quality of life during convalescence.

The COVID-19 pandemic brought new challenges to biomedical sciences, specifically, the development of effective therapeutics for prevention and treatment of acute viral and stress-induced diseases. Unfortunately, the potential of herbal preparations in prevention and treatment of viral infections is underestimated. Lack of solid evidence for efficacy and safety from randomized, controlled clinical studies is often cited as a reason for dismissal. In reality, the risk of adverse events is significantly higher for synthetic antiviral and immunotropic drugs than for the vast majority of herbal preparations. The COVID-19 pandemic, for which to date no cure or vaccine exist, thus provides a more than timely context in terms of findings related to epidemiology and pathogenesis in which to discuss relevant evidence from pre-clinical and clinical studies of herbal preparations, specifically adaptogens.

Pathogenesis and progression of a viral infection is a multistep process [1, 2] , which requires an appropriate therapeutic strategy starting with initiation of overall defense response to the pathogen [3] [4] [5] [6] . Included in this process are numerous extra-and intracellular interactions between components of host defense and life cycle regulation systems on all levels of regulation-genomic, transcriptomic, proteomic, metabolomic and macrobiotic [7] . Consequently, effective prevention or treatment of a viral infection and other viral infections requires pharmaceutical intervention affecting the innate and adaptive immune system, phases I-III metabolizing enzymes of detoxifying and repair systems, the innate and adaptive immune system, phases I-III metabolizing enzymes of detoxifying and repair systems, as well as the virus' life cycle and proliferation ( Figure 1 ). This can be achieved with herbal preparations that have polyvalent and pleiotropic actions on host defense systems. For instance, it was found that more than half of SARS-CoV-2-infected subjects were asymptomatic at the time of testing [8] , which points at the ability of the innate immune system to curb progression of COVID-19 at an early stage of invasion of the pathogen. Both activation and inhibition of various components of innate immune system [4, 5, 9] by numerous natural compounds of plant kingdom is well documented in many publications. Specifically, complex mixtures of natural compounds (or herbal extracts) synergistically targeting multiple elements of molecular networks involved in inflammatory defense response are presumably more effective than mono-drugs that target only one receptor [10, 11] . Adaptogens are natural stress-protective compounds or plant extracts that increase adaptability, resilience, and survival of organisms [12] . Adaptogens increase "the state of non-specific resistance" of organisms [13] to harm [14, 15] , including bacterial and viral pathogens. Non-specific defense responses to pathogens depend on the body′s ability to recognize conserved features of pathogens by the evolutionarily ancient innate immune system, a group of proteins and phagocytic cells, which become activated during the critical first hours and days of infection to destroy invaders [9] . The basic mechanisms of innate immune responses that regulate innate defense, e.g., pattern recognition by toll-like receptors (TLR), defensins, etc., are conserved and apparently involved in innate immunity in all multicellular organisms. Their conservation during evolution shows the importance of innate responses in the defense against microbial and viral pathogens [9] .

More than 100 medicinal plants have been reported to have adaptogenic activity, however only few, i.e., Adaptogens are natural stress-protective compounds or plant extracts that increase adaptability, resilience, and survival of organisms [12] . Adaptogens increase "the state of non-specific resistance" of organisms [13] to harm [14, 15] , including bacterial and viral pathogens. Non-specific defense responses to pathogens depend on the body s ability to recognize conserved features of pathogens by the evolutionarily ancient innate immune system, a group of proteins and phagocytic cells, which become activated during the critical first hours and days of infection to destroy invaders [9] . The basic mechanisms of innate immune responses that regulate innate defense, e.g., pattern recognition by toll-like receptors (TLR), defensins, etc., are conserved and apparently involved in innate immunity in all multicellular organisms. Their conservation during evolution shows the importance of innate responses in the defense against microbial and viral pathogens [9] . Comply with the key criterium, that is to exhibit multitarget effects on the neuroendocrine-immune system by triggering adaptive stress responses. These include stimulation of cellular and organismal defense systems, activation of intracellular and extracellular adaptive signaling pathways, and expression of stress-activated proteins to change protection or repair capacity and increase non-specific resistance and adaptation to stress [11, 12] .

Anti-inflammatory, antiviral, antioxidant and other related activity of plants referred to as adaptogenic have been demonstrated in numerous pre-clinical studies. Tables 1-5 and Figure 1 show multiple molecular targets identified for adaptogenic plant extracts exhibiting:

• Specific antiviral action-preventing viruses binding to host cells, and on non-structural (Nsps) and structural proteins involved in viral life cycle in infected host cells and replication of the virus; • Non-specific antiviral action by the effects on:

Innate immunity including activation of defensins, the complement system, upregulation of expression of pathogen's pattern recognition receptors, specifically TLR, and interferons; Downregulation of expression of pro-inflammatory cytokines IL-1, IL2, IL-6, IL-8, and TNF, activation of natural killer cells, mucous sentinel and phagocyting cells (mast cells, dendritic cells, macrophages, neutrophils, eosinophils, and basophils) and the melatonin signaling pathways; Adaptive immunity including T cells and MHC proteins, B cells and antibodies.

• N-terminal gene 1 protein (Nsp1) suppresses host innate immune response, inhibiting type-I interferon production and induces host mRNA degradation [24]; • Nsp3 (papain-like protease, PLpro) is essential for virus replication and to antagonize the host's innate immunity; • Nsp5 (3-chimotrypsin-like protease, 3CLpro) mediates viral replication, transcription and the maturation of Nsps, which is essential in the life cycle of the virus; • Nsp12 (PNA-dependent PNA polymerase enzyme, RdRp) is a conserved vital enzyme of the coronavirus replication/transcription complex; • Nsp13 (helicase enzyme) is a multifunctional protein necessary for the replication of coronavirus.

Nine structural and accessory proteins, including spike (S) and envelope (E) glycoproteins, membrane (M) and nucleocapsid (N) proteins, are probably most important in the search for inhibitors of their expression or functions [19] . The primary function of structural S proteins is to bind the S1 subunit with the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), and the S2 subunit with serine protease TMPRSS2, which mediates virus-cell and cell-cell membrane fusion. ACE2 has been identified as a functional receptor playing a crucial role in SARS coronavirus-induced lung injury [25, 26] . ACE2 is expressed in all tissues-particularly in pulmonary and heart tissues, where it is significantly increased in hypertensive patients continuously using ACE inhibitors and angiotensin 1 receptor (AT1R) blockers. This explains the higher death rate in elderly individuals with comorbidities such as hypertension, diabetes, and heart disease [27-30].

We have organized results of pre-clinical investigations into five groups: direct viricidal effects, specific antiviral actions, non-specific antiviral actions, anti-inflammatory effects and repair of oxidative stress-induced injuries in compromised cells and tissues, and other effects of potential relevance in the progression of viral infections. Outcomes are presented in Tables 1-5. They include results for aforementioned adaptogenic plant extracts and some of their active constituents: tetracyclic and pentacyclic triterpene glycosides (ginsenosides, withanolides, and glycyrrhizin), diterpene lactones (andrographolides), phenethyl-and phenylpropanoid glycosides (salidroside, rosavin, and eleutheroside B), and lignans (eleutheroside E, schisandrins, anwulignan, and ellagic acids). 

Results of 33 RCTs (7175 patients) with AP (as a monotherapy and as fixed combinations with other herbs) clinical studies were systematically reviewed. The meta-analysis shows that AP improved cough (n = 596, standardized mean difference SMD: −0.39, 95% confidence interval CI [−0.67, −0.10]) and sore throat. It has a statistically significant effect in improving overall symptoms of acute respiratory tract infections (ARTIs) when compared to placebo, usual care, and other herbal therapies. Evidence also suggested that AP (alone or plus usual care) shortened the duration of cough, sore throat and sick leave/time to resolution when compared versus usual care. No major adverse events (AEs) were reported, and minor AEs were mainly gastrointestinal [242] .

Efficacy and safety of andrographolide-containing preparations was studied in patients with common cold in Scandinavia, South America, and India by Hancke et al. [243] , Caceres et al. [244] , Melchior et al. [245] , and Saxena et al. [246] . These four randomized double-blind placebo-controlled trials cover in total 539 patients suffering from symptoms of common cold. Hancke et al. [243] found the efficacy and safety of AP tablets (1200 mg/day) to be superior to placebo. The intensity of symptoms and signs of rhinitis, sinus pain and headache were significantly lowered compared to placebo. No adverse events were reported. Melchior et al. [245] performed a randomized, double-blind, placebo-controlled, monocenter, parallel-group trial with AP (1020 mg/kg) in 50 patients suffering from common cold over 5 days. The sick leave days were significantly reduced after the second visit in the verum group compared to placebo, the number of patients feeling recovered was increased and the number of patients experienced with easier disease was detected also to be better than placebo. Caceres et al. [244] also tested the treatment of common cold with AP (1200 mg.dat) in a randomized, double-blind, placebo-controlled, monocenter, parallel-group trial with 158 participants over 5 days. The intensity of nearly all symptoms decreased significantly in the verum group. The active treatment was clearly superior to placebo, reducing the prevalence and intensity of symptoms without observed or reported adverse effects and thus revealed a positive benefit/risk ratio. Saxena et al. [246] tested an AP extract (200 mg/day, 60 mg of andrographolide for 5 days) in a randomized, double-blind placebo-controlled clinical study involving 223 patients with uncomplicated upper respiratory tract infections. Only in the verum group all symptoms improved significantly (p ≤ 0.05) except earache. The overall efficacy of KalmCold™ over placebo was 2.1-fold higher (p ≤ 0.05) than placebo.

Several epidemiological studies carried out in the Soviet Union during the 1970s demonstrate that ES extract, given prophylactically, can reduce human mortality rates during the influenza epidemics as well as typical complications of an influenza infection, such as pneumonia, bronchitis, and otitis [221, [247] [248] [249] .

In 1986, Shadrin et al. [250] reported the results of prophylactic treatment of 1376 patients with acute respiratory illnesses during the influenza virus epidemic. Typical complications of an influenza infection, such as pneumonia, bronchitis, genyantritis and otitis, were determined in this two-parallel-group, placebo-controlled, double-blind study with a 3-month long follow-up period. A significantly lower frequency of complications caused by infections was observed in the ES group compared to the placebo group (p < 0.05), indicating milder infection progression. The overall morbidity rate was also consistently lower in the ES group than in the placebo group, but the differences were not statistically significant. Two consecutive open-label clinical studies of ES extract were carried out in 764 children with respiratory viral infections. The morbidity rate decreased 3.6-fold in those 396 children treated with ES liquid extract for a month. After 2 years, a 2-3-fold lower morbidity was recorded in those receiving ES liquid extract for a month compared to the control group of 252 children [251] . In a similar study with children at pre-school age, prophylactic administration of ES extract decreased the morbidity rate by 30-40% [252] .

Clinical trials conducted with GS have focused functional dyspepsia, aphthous stomatitis, gastric and duodenal ulcers, postoperative sore throat, hyperlipidemia and antiatherogenic effects [207] . Since the publication of the EMA's assessment report, numerous further clinical trials have been conducted. A recent review by Kwon et al. [253] summarizes study results related to liver, gastrointestinal, oral, skin and metabolic disorders which confirm licorice's anti-inflammatory, antioxidant, and immunomodulatory properties. However, the authors caution against chronic use, especially in patients with cardiovascular comorbidities due to the mineralocorticoid-like effect of glycyrretinic acid and GS-induced pseudoaldosteronism.

PS has been extensively studied in clinical investigations of multiple adaptogenic indications [208] . Scaglione et al. [254] conducted a clinical trial of efficacy and safety of a PS extract for potentiating vaccination against the common cold and/or influenza syndrome in 227 volunteers and reported a significantly lower frequency of influenza or common cold the treatment group. The same group [255] reported significantly increased bacterial clearance in patients with chronic bronchitis who received PS extract concomitantly with antibiotic treatment. Lee et al. [256] conducted a clinical trial investigating the preventive activity of PS against acute respiratory illness (ARI) caused by viral infection in 100 volunteers and found ginseng to protect against contracting ARI, as well as decrease the duration and scores of ARI symptoms. Iqbal and Rhee [112] reviewed the evidence for antimicrobial activity of PS, specifically against pathogens causing respiratory infections from animal and in vitro models, as well as 15 clinical trials. Summarily, included investigations have shown PS to exert immunomodulatory activity, which reduces the level of proinflammatory cytokines and oxidative stress, which, in turn, reduce severity, duration, and frequency of symptoms and show potential for preventing development of respiratory infections.

Multiple clinicals trials on the effect of RR as a mono-product and in combinations on physical performance and stress-related fatigue have been conducted [209] , affirming the traditional use as an adaptogen. Chuang et al. [257] studied the effect of RR as an adjunct treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) and found it to significantly improve tidal breathing and ventilation efficiency. Zhang et al. [258] evaluated the effects of RR on the preventive treatment of Pharmaceuticals 2020, 13, 236 12 of 32 acute lung injury (ALI) caused by post-traumatic/inflammatory and thoracic-cardiovascular operations. They observed a significant decrease in Acute Respiratory Distress Syndrome complications and concluded that early use of RR may protect against risk factors of ALI/ARDS. This recommendation was later confirmed by Lu et al. [259] in a similar trial. Ahmed et al. [260] studied the antiviral properties of RR in marathon runners. RR induced antiviral activity early and delayed exercise-dependent increase in virus replication. RR's role in the treatment of ischemic heart disease was investigated by Yu et al. [261] in a meta-analysis of 13 clinical trials and found an overall positive effect on both improvement of symptoms and ECG.

Pre-clinical findings have been corroborated in numerous clinical investigations, specifically SC's effect in viral respiratory tract infections [212, 250, [262] [263] [264] , by targeting viral RNA synthesis and replication and stimulating innate and adaptive immunity, among others.

Tandon and Yadav [265] reviewed 30 human clinical trials, establishing reasonable safety and efficacy in subclinical hypothyroidism; chronic stress, insomnia and anxiety; cognitive improvement; fertility; and as a chemotherapy adjuvant, among others. Adaptogenic effects were studied in three clinical trials, one of which [266] reported significantly increased oxygen consumption, maximum velocity, and average absolute and relative power under exercise conditions with WS supplementation, an outcome that may be relevant in convalescence from respiratory disease.

The results of five randomized, double-blind placebo-controlled studies with a fixed combination of AP and ES (Kan Jang, KJ) conducted between 1997 and 2004 in Scandinavia, South America, Russia and Armenia suggest that it relieves symptoms of uncomplicated respiratory tract infections caused by common cold [267] [268] [269] [270] [271] without causing any safety concerns. Caceres et al. [267] investigated the prevention of common cold in a randomized, double-blind, placebo-controlled, monocenter, parallel-group trial with 107 participants over 3 months. KJ showed a significantly reduced incidence rate of cold compared to placebo after three months. Melchior et al. [270] investigated KJ in two randomized, double-blind, placebo-controlled, monocenter, parallel-group, pilot and phase III clinical trials with correspondingly 46 and 179 participants for a maximum of 8 days (pilot study) and followed by a phase III study for 3 days in the treatment of uncomplicated upper respiratory tract infections. In the pilot study, the active therapy by Kan Jang was superior to placebo in the reduction in the total scores for all symptoms after 5 days. In the phase III study, the symptom score was more significantly improved in the treatment group compared to placebo. Gabrielian et al. [268] investigated KJ in a double-blind, placebo-controlled, multicenter, parallel-group trial in 185 participants with acute upper respiratory tract infections including sinusitis over 5 days. KJ was found to be a valuable therapeutic option and to have a positive benefit/risk ratio for the treatment of acute upper respiratory tract infections and for relief of inflammatory symptoms of sinusitis. Kulichenko et al. [269] investigated KJ in two randomized, comparator-controlled, open multicenter, parallel-group trials with 540 participants over 3 to 5 days in a pilot study, followed by a phase III study for 5 days in the treatment of uncomplicated upper respiratory infections. KJ was found to be superior in alleviation of symptoms such as headache, myalgia and conjunctivitis. Spasov et al. [271] investigated KJ in a randomized controlled three parallel-group study in 130 children with uncomplicated common cold over a period of 10 days. The amount of nasal secretion g/day and nasal congestion g/day and nasal congestion decreased significantly, and recovery time was significantly accelerated by KJ compared to Immunal and standard therapy. Kan Jang was well tolerated, and no side effects were observed in this group.

The postmarketing pharmacovigilance assessment of KJ shows a favorable benefit/risk ratio. Only 37 adverse event reports (mainly to allergic reactions) to the Swedish and Danish competent Pharmaceuticals 2020, 13, 236 13 of 32 authorities were recorded in 23 years with over 20 million doses of KJ sold. This equates to one adverse event in approximately 100,000 patients, assuming an average drug uptake for 5 consecutive days [272] .

Another promising tool to non-specifically curb SARS-induced progression of inflammation, particularly in elderly subjects, with adaptogens is to utilize their capacity to activate the melatonin signaling pathway.

In a recent study of the molecular mechanisms of action of adaptogens, it was found that they activate the melatonin signaling pathway by acting through two G protein-coupled membrane receptors MT1 and MT2 and upregulation of the ligand-specific nuclear receptor gene RORA [11] which encodes retinoic acid receptor (RAR)-related orphan nuclear receptor alpha (RORα)-a multifunctional transcription activating factor involved in many physiological processes, including regulation of immunity and metabolism, as well as playing an important role in several pathologies, including inflammation, autoimmune diseases, asthma, osteoporosis, cancer, and metabolic syndrome [202, [273] [274] [275] .

Furthermore, the molecular mechanism of actions of melatonin [276, 277] and adaptogens are alike in terms of their effects on expression of many genes including UCN, GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2, RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10, MERTK, PRKCH, and TTN, suggesting that melatonin is an adaptation hormone [278, 279] , playing an important role in regulation of homeostasis [11] . This conclusion is in line with the common opinion about its physiological role and functions with pleiotropic actions in human, animals, and plants, which include controlling senescence and aging, regulating circadian rhythms, defense response to pathogens and bolstering the immune system [202, 277, [280] [281] [282] [283] .

The concentration of melatonin in human serum significantly increases at nighttime from 15-20 to 30-180 pg/mL. However, with age, the level of night melatonin does not increase higher than 30 pg/mL [284] . The decreased ability to produce melatonin with aging is probably associated with low-grade chronic inflammation and aging-related diseases. Melatonin has been shown to exert anti-inflammatory, antioxidant, and other beneficial actions in aging [202] .

Melatonin has been found not only in humans, but also in bacteria, mammals, birds, amphibians, reptiles, fish, and plants. The richest plant sources of melatonin are Coffea spp. with 5800-6500 ng/g [285] , Tanacetum parthenium (L.) Sch. Bip. with 2450 ng/g, Viola philipica Cav. with 2368 ng/g, Uncaria rhynchophylla (Miq.) Jacks. with 2460 ng/g, Hypericum perforatum L. with 4390 ng/g, and Morus alba L. with 1510 ng/g, to name just a few [283, 286] . Some adaptogens also contain melatonin in amounts of 100-500 mg/g, e.g., AP with 511 ng/g, PS with 169 ng/g, SC with 86 ng/g, and GS with 112 ng/g [283, 286] , and therefore effects of adaptogens on the melatonin signaling pathways may in part be due to its presence. However, other adaptogenic plants, such as RR, ES, and WS, do not contain melatonin, but nonetheless significantly activate the melatonin signaling pathway and upregulate RORA expression [11] .

While the content of melatonin in the plants studied ranged from 0.01 to 6500 ng/g dry weight [283, [286] [287] [288] [289] , assuming a therapeutic daily dose in the range from 1 to 10 g of dry herbal substance, the consumed melatonin (<0.065 mg) would be significantly lower than its therapeutic daily dose of 3-10 mg. However, these contents are in the range of daily amount (30 µg) of melatonin synthesized in adult humans. Since oral bioavailability of melatonin is approximately 3% in 27-year-old heathy subjects [290] , the consumption of 10 g of dry herbal substance containing 1000 ng/g of melatonin can increase its concentration in blood to approximately 12 pg/mL, which is comparable to physiological concentrations of endogenous melatonin in the blood, particularly in elderly people 60-70 years of age, from 15 pg/mL at daytime to 30 pg/mL at nighttime [284] .

Recently, melatonin was prioritized as a potential SARS-CoV-2 repurposable drug using network pharmacology-based methodologies that quantify the interplay between the virus-host interactome and drug targets in the virus-host protein interactions network [23, 291] . This conclusion aligns with results of other studies summarized in several reviews [292] [293] [294] . For instance, melatonin was found to exhibit therapeutic potential in influenza A H1N1 virus infection, to elicit anti-inflammatory and immune modulatory effects-the induction of IL-10 by melatonin occurs via the upregulation of IL-27 in DC-and to exhibit a synergistic effect with an antiviral drug [295] . In another study, intranasally inoculating mice with RSV resulted in oxidative stress changes by increasing NO, MDA and -OH levels, and decreasing GSH and SOD activities. Administration of melatonin significantly reversed all these effects. Furthermore, melatonin inhibited the production of proinflammatory cytokines such as TNFα in serum of RSV-infected mice. These results suggest that melatonin ameliorates RSV-induced lung inflammatory injury in mice via inhibition of oxidative stress and proinflammatory cytokine production and may indeed be considered a novel therapeutic agent in virus-induced pulmonary infection [296] . Melatonin was also found to exert direct viricidal effects against respiratory syncytial virus [296, 297] , Semliki Forest virus [298] and Venezuelan equine encephalomyelitis virus [299] [300] [301] .

These effects may be partially associated with melatonin-induced upregulation of RORA encoding RORα in the liver, thymus, brain, skeletal muscle, skin, lung, adipose tissue, and kidney. RORα has an anti-inflammatory function in human macrophages. In RORA-deleted cells, a dramatic increase in basal expression of a subset of NF-κB-regulated genes, including TNF, IL-1β and IL-6, at both transcriptional and translational levels was observed [302] . The expression of RORα1 inhibits TNFα-induced IL-6, IL-8 and COX-2 expression in primary smooth-muscle cells [303] and plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and in cytokine production in the ILC3 and Th17 cells [274, [304] [305] [306] . While RORα is a known inhibitor of NF-κB proinflammatory signaling, it can also be utilized by highly pathogenic influenza H5N1 virus, which can inhibit inflammatory response in monocytes via activation of RORα and therefore prevent an effective inflammatory defense response of monocytes [307] .

From the data presented here, it can be concluded that adaptogens can play a potentially important role at all stages of viral infection. Adopting a recently proposed phased immunophysiological approach to viral infection [308] , adaptogens exerting multitarget effects on the neuroendocrine-immune system by triggering adaptive stress responses have a place in prevention, infection, escalating inflammation and recovery ( Figure 2 ). They provide baseline support through their immunomodulatory, immunostimulatory, and antioxidant effect through all four phases, combat infection through their specific and non-specific antiviral properties, alleviate escalating inflammation through their anti-inflammatory effects, as well as their capacity to repair oxidative stress-induced injuries in compromised cells and tissues, and address secondary disease states and comorbidities through various, infection-related activities.

Another possible benefit of adaptogens in COVID-19 is their effect during convalescence of patients. This is based on the results of an RCT with Chisan/ADAPT-232, a fixed combination of ES with RR and SC in pneumonia [309] . Adjuvant therapy with ADAPT-232 had a positive effect on the recovery of patients by decreasing the duration of the acute phase of the illness, by increasing mental performance of patients in the rehabilitation period, and by improving their quality of life. 

Where available, assessment reports published by the European Medicines Agency (EMA)'s Herbal Medicinal Products Committee (HMPC) were consulted to provide the summaries below. To cover the time elapsed since publication of these reports and in all other cases, database searches in PubMed, Scopus and Google Scholar were performed. Keywords included scientific and common 

Where available, assessment reports published by the European Medicines Agency (EMA)'s Herbal Medicinal Products Committee (HMPC) were consulted to provide the summaries below.

To cover the time elapsed since publication of these reports and in all other cases, database searches in PubMed, Scopus and Google Scholar were performed. Keywords included scientific and common plant names, in combination with "antiviral", "adaptogen *", "respiratory", "human", and "clinical trial". Relevant primary literature referenced in reviews was retrieved manually. Independent searches were performed regarding relevant information on SARS-CoV-2 and COVID-19, as well as the evidence for therapeutic relevance of phytomedicines in COVID-19. 

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Schisandrin Attenuates Lipopolysaccharide-Induced Lung Injury by Regulating TLR-4 and Akt/FoxO1 Signaling Pathways

Schisandra polysaccharide evokes immunomodulatory activity through TLR 4-mediated activation of macrophages

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Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll-like receptor signaling pathway

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Prospects of immunostimulating vaccination against influenza including the use of Eleutherococcus and other preparations of plant origin

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A comparative study on root and bark extracts of Eleutherococcus senticosus and their effects on human macrophages

Adaptogens: Tonic Herbs for Fatigue and Stress

Ginsenoside Rb1 attenuates intestinal ischemia/reperfusion-induced inflammation and oxidative stress via activation of the PI3K/Akt/Nrf2 signaling pathway

Ginseng alleviates microbial infections of the respiratory tract: A review

Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation

Molecular insight in the multifunctional activities of Withaferin

Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis

The synthesis of Rantes, G-CSF, IL-4, IL-5, IL-6, IL-12 and IL-13 in human whole-blood cultures is modulated by an extract from Eleutherococcus senticosus L. roots

Effect of Withania somnifer on CD38 expression on CD8+ T lymphocytes among patients of HIV infection

Inhibition of Group IIA Secretory Phospholipase A2 and its Inflammatory Reactions in Mice by Ethanolic Extract of Andrographis paniculata, a Well-known Medicinal Food

Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer

Multipathway Integrated Adjustment Mechanism of Glycyrrhiza Triterpenes Curing Gastric Ulcer in Rats

Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway

Blood pressure-lowering effect of Korean red ginseng associated with decreased circulating Lp-PLA 2 activity and lysophosphatidylcholines and increased dihydrobiopterin level in prehypertensive subjects

Anti-platelet role of Korean ginseng and ginsenosides in cardiovascular diseases

20(S)-Protopanaxatriol inhibits release of inflammatory mediators in immunoglobulin E-mediated mast cell activation

Inhibitory effects of thromboxane A2 generation by ginsenoside Ro due to attenuation of cytosolic phospholipase A2 phosphorylation and arachidonic acid release

Anti-inflammatory activity of Rhodiola rosea-"A second-generation adaptogen

Effect of Gomisin A (TJN-101) on the Arachidonic Acid Cascade in Macrophages

Natural phospholipase A2 myotoxin inhibitor proteins from snakes, mammals and plants

Purification of a post-synaptic neurotoxic phospholipase A2 from Naja naja venom and its inhibition by a glycoprotein from Withania somnifera

Evaluating the inhibitory potential of Withania somnifera on platelet aggregation and inflammation enzymes: An in vitro and in silico study

The production of nitric oxide and prostaglandin E2 in peritoneal macrophages is inhibited by Andrographis paniculata, Angelica sinensis and Morus alba ethyl acetate fractions

Effects of anti-inflammatory and adaptogenic herbal extracts on gene expression of eicosanoids signaling pathways in isolated brain cells

Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation

14-deoxyandrographolide as a platelet activating factor antagonist in bovine neutrophils

Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng

Lignans with platelet activating factor antagonist activity from Schisandra chinensis (Turcz.) Baill

Structure-Activity Relationships of Lignans from Schisandra chinensis as Platelet Activating Factor Antagonists

Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide

The Adaptogens Rhodiola and Schizandra Modify the Response to Immobilization Stress in Rabbits by Suppressing the Increase of Phosphorylated Stress-activated Protein Kinase

Overview of pharmacological activities of Andrographis paniculata and its major compound andrographolide

Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-κB pathway

Polysaccharides from Acanthopanax senticosus enhances intestinal integrity through inhibiting TLR4/NF-κB signaling pathways in lipopolysaccharide-challenged mice

Acanthoic acid inhibits IL-8 production via MAPKs and NF-κB in a TNF-α-stimulated human intestinal epithelial cell line

Protective effect of Acanthopanax senticosus extract against endotoxic shock in mice

Inhibition of inducible nitric oxide synthase by Acanthopanax senticosus extract in RAW264.7 macrophages

Acanthopanax senticosus has a heme oxygenase-1 signaling-dependent effect on Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages

Protective effects of Acanthopanax vs. Ulinastatin against severe acute pancreatitis-induced brain injury in rats

+)-Syringaresinol-di -O-β-d-glucoside, a phenolic compound from Acanthopanax senticosus Harms, suppresses proinflammatory mediators in SW982 human synovial sarcoma cells by inhibiting activating protein-1 and/or nuclear factor-κB activities

Protective effects of syringin against lipopolysaccharide-induced acute lung injury in mice

Red ginseng extract regulates differentiation of monocytes to macrophage and inflammatory signalings in human monocytes

20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factor-κB in RAW 264.7 macrophages stimulated with lipopolysaccharide

Effects of Selected Ginsenosides on Phorbol Ester-Induced Expression of Cyclooxygenase-2 and Activation of NF-κB and ERK1/2 in Mouse Skin

Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax ginseng C.A. Meyer

Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-κB activation and tumor promotion

Rhodiola rosea L. modulates inflammatory processes in a CRH-activated BV2 cell model

Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs

Salidroside Inhibits Lipopolysaccharide-ethanol-induced Activation of Proinflammatory Macrophages via Notch Signaling Pathway

Salidroside protects against bleomycin-induced pulmonary fibrosis: Activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-β1/Smad-2/-3 pathways

Protective effects of Rosavin on bleomycin-induced pulmonary fibrosis via suppressing fibrotic and inflammatory signaling pathways in mice

Salidroside inhibits MAPK, NF-κB, and STAT3 pathways in psoriasis-associated oxidative stress via SIRT1 activation

Salidroside Protects Against Advanced Glycation End Products-Induced Vascular Endothelial Dysfunction

Salidroside Reduces Inflammation and Brain Injury After Permanent Middle Cerebral Artery Occlusion in Rats by Regulating PI3K/PKB/Nrf2/NFκB Signaling Rather than Complement C3 Activity

Schisantherin A Exhibits Anti-inflammatory Properties by Down-Regulating NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Treated RAW 264.7 Cells. Inflammation

Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling

Schisandra Chinensis Lignans Suppresses the Production of Inflammatory Mediators Regulated by NF-κB, AP-1, and IRF3 in Lipopolysaccharide-Stimulated RAW264.7 Cells. Molecules

Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF-κB and MAPK signal pathways

Extract of Fructus Schisandrae chinensis Inhibits Neuroinflammation Mediator Production from Microglia via NF-κ B and MAPK Pathways

Vanden Berghe, W. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ

Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation

Withaferin A inhibits tumor necrosis factor-α-induced expression of cell adhesion molecules by inactivation of Akt and NF-κB in human pulmonary epithelial cells

Withania somnifera inhibits NF-κB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells

Melatonin ameliorates H 2 O 2 -induced oxidative stress through modulation of Erk/Akt/NFkB pathway

The Protective Effect of the Ethanol Leaf Extract of Andrographis Paniculata on Cisplatin-Induced Acute Kidney Injury in Rats Through nrf2/KIM-1 Signalling Pathway

Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells

Andrographolide inhibits hypoxia-induced HIF-1α-driven endothelin 1 secretion by activating Nrf2/HO-1 and promoting the expression of prolyl hydroxylases 2/3 in human endothelial cells

Andrographolide inhibits TNFα-induced ICAM-1 expression via suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression through the PI3K/Akt/Nrf2 and PI3K/Akt/AP-1 pathways in human endothelial cells

a Natural Antioxidant: An Update. Antioxidants

Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway

Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aβ 42 through Nrf2-Related Inflammatory Response

Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action

Andrographolide induces Nrf2 and heme oxygenase 1 in astrocytes by activating p38 MAPK and ERK

The protective effects of Acanthopanax senticosus Harms aqueous extracts against oxidative stress: Role of Nrf2 and antioxidant enzymes

Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol-and CCl4-induced hepatic fibrosis

Pharmacodynamics of Ginsenosides: Antioxidant Activities, Activation of Nrf2, and Potential Synergistic Effects of Combinations

Ginsenoside Rb 1: A novel therapeutic agent in Staphylococcus aureus-induced Acute Lung Injury with special reference to Oxidative stress and Apoptosis

Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2-related factor 2 pathway

Salidroside Protects Dopaminergic Neurons by Preserving Complex I Activity via DJ-1/Nrf2-Mediated Antioxidant Pathway

Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

Protective effect of Anwulignan against D-galactose-induced hepatic injury through activating p38 MAPK-Nrf2-HO-1 pathway in mice

Antioxidative and Cardioprotective Effects of Schisandra chinensis Bee Pollen Extract on Isoprenaline-Induced Myocardial Infarction in Rats

Anti-fatigue effect of anwulignan via the NRF2 and PGC-1α signaling pathway in mice

Withaferin A induces heme oxygenase (HO-1) expression in endothelial cells via activation of the Keap1/Nrf2 pathway

Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms. Free Radic

Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. Free Radic

Melatonin Attenuates Memory Impairment Induced by Klotho Gene Deficiency Via Interactive Signaling Between MT2 Receptor, ERK, and Nrf2-Related Antioxidant Potential

Ginseng and heme oxygenase-1: The link between an old herb and a new protective system

Evaluation of molecular chaperons Hsp72 and neuropeptide Y as characteristic markers of adaptogenic activity of plant extracts

Adaptogens exert a stress-protective effect by modulation of expression of molecular chaperones

Adaptogens Stimulate Neuropeptide Y and Hsp72 Expression and Release in Neuroglia Cells

Buffering the immune system

The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury

Reverse Ayurvedic Pharmacology of Ashwagandha as an Adaptogenic Anti-Diabetic Plant: A Pilot Study

Adaptogenic potential of andrographolide: An active principle of the king of bitters (Andrographis paniculata)

Immunopotentiating significance of conventionally used plant adaptogens as modulators in biochemical and molecular signalling pathways in cell mediated processes

Assessment Report on Glycyrrhiza Glabra L. and/or Glycyrrhiza Inflata Bat. and/or Glycyrrhiza Uralensis Fisch

Radix; Committee on Herbal Medicinal Products (HMPC). European Medicines Agency

Committee on Herbal Medicinal Products (HMPC). European Medicines Agency

Schisandra chinensis (Turcz.) Baill. Fitoterapia

Potential of Schisandra chinensis (Turcz.) Baill. in Human Health and Nutrition: A Review of Current Knowledge and Therapeutic Perspectives

Pharmacology of Schisandra chinensis Bail.: An overview of Russian research and uses in medicine

Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: A review on the bioactive components, pharmacological properties, analytical and biotechnological studies

Pharmacologic overview of Withania somnifera, the Indian Ginseng

Withania somnifera (Linn.) Dunal: A review of chemical and pharmacological diversity

Metabolomic and biotechnological approaches to determine therapeutic potential of Withania somnifera (L.) Dunal: A review

Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats

Inhibition of α-Glucosidase by Andrographis paniculata. Ethanol Extract in Rats

Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats

Antihyperglycaemic and anti-oxidant properties of andrographis paniculata in normal and diabetic rats

Radix; Committee on Herbal Medicinal Products (HMPC). European Medicines Agency

Absorption of andrographolides from Andrographis paniculata and its effect on CCl4-induced oxidative stress in rats

Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent andrographolide

Antioxidant action of Andrographis paniculata on lymphoma

Protective Effect of Andrographis paniculata and Andrographolide on Cyclophosphamide-Induced Urothelial Toxicity

A biochemical study on the gastroprotective effect of andrographolide in rats induced with gastric ulcer

Antioxidant and gastroprotective activities of Andrographis paniculata (Hempedu Bumi) in Sprague Dawley rats

Antihepatotoxic Activity of Diterpenes of Andrographis Paniculata (Kal-Megh) Against Plasmodium Berghei-Induced Hepatic Damage in Mastomys Natalensis

Andrographis paniculata ameliorates carbon tetrachloride (CCl4)-dependent hepatic damage and toxicity: Diminution of oxidative stress

Hepatoprotective activity of Andrographis Paniculata and Swertia Chirayita

Hepatoprotective effect of Andrographis paniculata and its constituent, andrographolide, on ethanol hepatotoxicity in rats

Prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata nees and fish oil. Experimental studies of effects and mechanisms

Mechanisms of cardiovascular activity of Andrographis paniculata in the anaesthetized rat

Antiangiogenic activity of Andrographis paniculata extract and andrographolide

Modulation of Natural Killer Cell Activity, Antibody-Dependent Cellular Cytotoxicity, and Antibody-Dependent Complement-Mediated Cytotoxicity by Andrographolide in Normal and Ehrlich Ascites Carcinoma-Bearing Mice. Integr. Cancer Ther

Activation of Cytotoxic T Lymphocyte Responses and Attenuation of Tumor Growth in vivo by Andrographis paniculata Extract and Andrographolide

Studies on psychopharmacological activity ofAndrographis paniculata extract

Protective Effects of Andrographis paniculata Extract and Pure Andrographolide Against Chronic Stress-Triggered Pathologies in Rats

Andrographolide Exerts Significant Antidepressant-Like Effects Involving the Hippocampal BDNF System in Mice

Rhodiola rosea L. as a putative botanical antidepressant

Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression

Andrographis paniculata (Chuān Xīn Lián) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis

A double-blind study with a new monodrug Kan Jang: Decrease of symptoms and improvement in the recovery from common colds

Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study

Controlled clinical study of standardized Andrographis paniculata extract in common cold-A pilot trial

A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold™) in patients with uncomplicated upper respiratory tract infection

Eleutherococcus in the Prophylaxis of the disease incidence in the Arctic

Eleutherococcus in preventive maintenance of a flu and relapses of hypertonic illness

Tentative data on the mass Eleutherococcus prophylaxis of influenza at the main assembly line and metallurgic plant of the Volga Automobile Plant

Estimation of prophylactic and immunostimulating effects of Eleutherococcus and Schizandra chinensis preparations

Effect of Eleutherococcus on respiratory viral infectious morbidity in children in organized collectives

Effect of preventive administration of Eleutherococcus extract on health of children under school age

A Review of the Pharmacological Efficacy and Safety of Licorice Root from Corroborative Clinical Trial Findings

Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold

Effects of the Standardised Ginseng Extract G115®in Patients with Chronic Bronchitis

Preventive Effect of Korean Red Ginseng for Acute Respiratory Illness: A Randomized and Double-Blind Clinical Trial

Adjunctive Treatment with Rhodiola Crenulata in Patients with Chronic Obstructive Pulmonary Disease-A Randomized Placebo Controlled Double Blind Clinical Trial

Early use of Chinese drug rhodiola compound for patients with post-trauma and inflammation in prevention of ALI/ARDS

Early use of Chinese drug rhodiola compound for patients with thoracic operation inprevention of ALI

Rhodiola rosea exerts antiviral activity in athletes following a competitive marathon race. Front

The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: A systematic review and meta-analysis of randomized controlled trials

The effect of Schisandra seed tincture on morbidity rate among workers of Chirick shoe factory during the 1969 influenza epidemic

Schizandra seed tincture and dibazole as means of non-specific prophylaxis of acute respiratory infections during the peak of influenza at the beginning of 1969

Pneumonia in aged and old people in conditions of the monsoon climate of the southern Primorskij region

Far East Branch of the USSR Academy of Science

Safety and clinical effectiveness of Withania Somnifera (Linn.) Dunal root in human ailments

Effects of Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) on physical performance and cardiorespiratory endurance in healthy young adults

Prevention of common colds with Andrographis paniculata dried extract. A pilot double blind trial

A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis

Controlled Study of Kan Jang versus Amantadine in the Treatment of Influenza in Volgograd

Double-blind, placebo-controlled pilot and Phase III study of activity of standardized Andrographis paniculata Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection

Comparative controlled study of Andrographis paniculata fixed combination, Kan Jang®and an Echinacea preparation as adjuvant, in the treatment of uncomplicated respiratory disease in children

Periodic Safety Update Report for Kan Jang

Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism

REV-ERB and ROR nuclear receptors as drug targets

Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes

Melatonin as a master regulator of cell death and inflammation: Molecular mechanisms and clinical implications for newborn care

Pineal hormone melatonin is an universal adaptogenic agent

Melatonin and the Immune System Therapeutic Potential in Cancer, Viral Diseases, and Immunodeficiency States. In The Pineal Gland and Cancer: Neuroimmunoendocrine Mechanisms in Malignancy

Melatonin and its relationship to plant hormones

Melatonin: A Multifunctional Factor in Plants

Aging, Melatonin, and the Pro-and Anti-Inflammatory Networks

Melatonin: Current Status and Future Perspectives in Plant Science

Melatonin, human aging, and age-related diseases

The physiological function of melatonin in plants

Melatonin in Chinese medicinal herbs

The potential of phytomelatonin as a nutraceutical

High levels of melatonin in the seeds of edible plants: Possible function in germ tissue protection

Development of a Phytomelatonin-Rich Extract from Cultured Plants with Excellent Biochemical and Functional Properties as an Alternative to Synthetic Melatonin

Gögenur, I. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Roles in influenza, Covid-19, and other viral infections

Can melatonin reduce the severity of COVID-19 pandemic?

COVID-19: Melatonin as a potential adjuvant treatment

Melatonin possesses an anti-influenza potential through its immune modulatory effect

Inhibitory effect of melatonin on lung oxidative stress induced by respiratory syncytial virus infection in mice

Melatonin: Its possible role in the management of viral infections-a brief review

Protective effects of melatonin in mice infected with encephalitis viruses

Melatonin prolongs survival of immunodepressed mice infected with the Venezuelan equine encephalomyelitis virus

Melatonin and viral infections

Melatonin protects mice infected with Venezuelan equine encephalomyelitis virus

RORα controls inflammatory state of human macrophages

The orphan nuclear receptor RORα is a negative regulator of the inflammatory response

Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures

Retinoic-Acid-Receptor-Related Orphan Nuclear Receptor Alpha Is Required for Natural Helper Cell Development and Allergic Inflammation

The orphan nuclear receptor ROR alpha and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease

Highly Pathogenic Influenza Viruses Inhibit Inflammatory Response in Monocytes via Activation of Rar-Related Orphan Receptor RORa

Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 from Prevention through Recovery

Impact of Chisan®(ADAPT-232) on the quality-of-life and its efficacy as an adjuvant in the treatment of acute non-specific pneumonia

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license

Authors gratefully acknowledge Patti Rowland for her assistance with creating the figures.

The authors declare no conflict of interest.