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FluEEZ Nasal

Viruses mutate at a much faster pace than their hosts. This is particularly true for RNA viruses such as influenza viruses and corona-viruses. It poses as a seemingly indomitable challenge for drug and vaccine makers. Currently approved ones, as many of you know, leave much room for improvement.

On the other hand, some, if not most, of the greatest medicines in human history came from nature --- aspirin, morphine, quinine, penicillin, metformin, artemisinin, the list goes on. Many of them are anti-infectives (which include anti-bacterials, antibiotics, anti-fungals, anti-protozoals, and anti-virals). Over the long history of traditional Chinese medicine (TCM), it has played a crucial role in helping the Chinese to overcome countless epidemics over the millennia, most notably during the 2002-2003 SARS epidemic. As a result, TCM was adopted from the very beginning of COVID-19 pandemic in China. National statistics showed that 91.5% of all patients used TCM.

 

In recent years, increasingly more scientific and clinical research data have substantiated the anti-viral power of a number of herbal products, often acting through distinct mechanisms of action, such as inducing interferons (key players of host anti-viral defense) and other enhancements of host immune function (see references below). Furthermore, biomedical researchers on COVID-19 in the past few months has yielded exciting new evidence that may explain the anti-viral power of herbal ingredients (see below).

Over the last 20 years we have always paid attention to the key role of nasal passage, which is often the first line of our defense against viruses and where pathogens may creep in. We have developed a nasal spray product, FluEEZ Nasal, to boost the immune function of this first line of defense, and to great reviews.  In April 2020, a collaboration of Bristish and French scientists published a paper on Nature Medicine revealing that SARS-CoV-2 likely uses two nose cell types for entry into human [2]. We were not surprised. For FluEEZ Nasal, we have chosen concentrated extracts of four remarkable herbs to make one exceptional spray, for flu, cold, and other viruses. Here's the list of reasons why it stands out:

  • FluEEZ Nasal has been successfully used and continuously perfected over the last two decades in Boston area integrative healthcare clinics. It is made of concentrated/standardized extracts from four herbs, each of which is chosen for its unique property and function, based on traditional medicine expertise and latest biomedical research. It is bottled as a nasal spray for convenient usage.

  • The selection and the carefully balanced proportion of these ingredients draw from the wisdom of traditional Chinese medicine, based on how they've been used in age-old formulae. Interestingly, according the latest version of "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia" published by China's State Health Commission, herbs that we used have also been selected for recommended TCM formulae. Most importantly, we do NOT use herbs banned by the FDA, as some of those recommended formulae, such as Ma Huang and Xixin. Nor do we use possibly harmful herbs including Bing Lang, Kuan Dong Hua, and Ze Xie.

  • Amazingly, in the past few months researchers have added evidence by showing that main compounds in our ingredients may:

    • bind to SARS-CoV-2's highly conserved main protease, 3CLpro, indispensable for the replication of coronaviruses, and, amazingly, is perfectly ensconced in the core of the substrate-binding pocket, acting as a “shield” in front of the catalytic residues to prevent the peptide substrate approaching the active site (Scutellaria baicalin and baicalein)[3].

    • bind to angiotensin-converting enzyme II (ACE2), in addition to the ability to down-regulate pro-inflammatory cytokines, inhibit the accumulation of intracellular reactive oxygen species (ROS), inhibit thrombin, inhibit the hyperproduction of airway exudates, and induce endogenous interferon (Licorice glycyrrhizin)[4].

  • FluEEZ Nasal, along with FluEEZ, successfully underwent rigorous in vitro and in vivo anti-influenza-virus studies from 1999 - 2000 (research results are available upon request).  Most importantly, it has been continuously used and highly valued for 20 years in Boston area integrative healthcare clinics.

REFERENCES:

[2] Sungnak, W., Huang, N., Bécavin, C. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med (2020). https://doi.org/10.1038/s41591-020-0868-6

[3] Su H. et al, Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro. bioRxiv doi: https://doi.org/10.1101/2020.04.13.038687

[4] Luo P, Liu D, Li J. Pharmacologic perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19 [published online ahead of print, 2020 Apr 23]. Int J Antimicrob Agents. 2020;105995. doi:10.1016/j.ijantimicag.2020.105995

See below for research data around these herbs. 

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Licorice Extract (26% Glycyrrhizin)

 

The main compound glycyrrhizin (aka glycyrrhizic acid) extracted from licorice root has antiviral and antibacterial effects. Cinatl J et al. [6] compared the effects of glycyrrhizin, as compared to classic antiviral drugs ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, on SARS-CoV. The results show that glycyrrhizin is the most active in inhibiting replication of the SARS-associated coronavirus. Research from Hoever G et al. [7] also shows that glycyrrhizin and some of its derivatives have good anti-SARS-CoV effect. As we know, SARS-CoV-2 and SARS-CoV are similar and their encoded proteins are 95% - 100% homologous. In another study, glycyrrhizin is shown to promote T cell production of IFN-γ [8].

Recent studies have shown that SARS-CoV-2 and SARS-CoV use the same host receptor, ACE2 (angiotensin-converting enzyme 2), and glycyrrhizic acid can bind to ACE2 [9]. Another study shows that glycyrrhizic acid has an inhibitory effect on HIV propagation [10]. Moreover, licorice contains volatile oils, among which thymol and carvacrol have significant antiviral and bactericidal effects [11]. Not surprisingly, licorice is a key ingredient in three popular TCM formulae, Lian-Hua-Qing-Wen(连花清瘟), Gan-Cao-Gan-Jiang(甘草干姜)as well as Jin-Hua-Qing-Gan (金花清感)decoctions.

REFERENCES:

[6] Cinatl J,Rabenau H,Morgenstern B,et al. Glycyrrhizin,an active component of liquorice roots,and replication of SARS-associated coronavirus[J]. Lancet, 2003,361(9374):2045-2046.

[7] Hoever G,Baltina L,Michaelis M,et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus[J]. J Med Chem,2005,48(4):1256-1259.

[8] Utsunomiya T,Kobayashi M,Pollard RB,et al. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus[J]. Antimicrob Agents Chemother,1997,41(3):551-556.

[9] Chen HS,Du QH. Potential natural compounds for preventing 2019-nCoV infection [J/OL]. Preprints,2020,1-13.

[10] Sasaki H,Takei M,Kobayashi M,et al. Effect of glycyrrhizin, an active component of licorice roots, on HIV replication in cultures of peripheral blood mono-nuclear cells from HIV-seropositive patients [J ]. Pathobiology,2002,70(4):229-236.

[11] Farag MA,Wessjohann LA. Volatiles profiling in medicinal licorice roots using steam distillation and solid-phase microextraction (SPME )coupled to chemometrics[J ]. J Food Sci,2012,77 (11): 1179-1184.

Scutellaria Extract

Scutellaria baicalensis is a key component of several patented TCM medicines in China, including Shuang-Huang-Lian (双黄连) and Qing-Fei-Pai-Du (清肺排毒)decoctions that are highly recommended for the pandemic in China. It has the effect of “clearing heat and dampness, and treats lung heat cough, dampness”, etc. in the paradigm of TCM.

 

Scutellaria can regulate immune system and inhibit overactive autoimmune responses. Th17 T cells play a key role in autoimmune diseases. Th17 up-regulation aggravates bronchus, lung inflammation and asthma attacks, whereas IFN-γ, IL- 4 are inhibitors of Th17 cell differentiation [12]. Baicalin from scutellaria can inhibit the secretion of IL-17A and IL-6, promote the secretion of IL-10, reduce pulmonary inflammation, inhibit mucus secretion, and protect mice with Th17 / Treg related allergic asthma [13]. Baicalin from scutellaria can also improve the pathological changes of pulmonary bronchitis and emphysema in rats, regulate the expression of INF-α in lung tissues, and have preventative and therapeutic effect for chronic obstructive pulmonary disease (COPD) in rats [14].

 

Preliminary autopsy conducted by Professor Liu Liang's team found that COVID-19 can cause a large amount of very thick mucus exudation in patients' alveoli [15], which would explain the "ground glass opacity" in the lungs of COVID-19 patients as revealed by imaging. Since Baicalin can inhibit fibroblast proliferation and inflammation, it can be helpful with the inflammatory fibrosis of the lung [16].  In addition, baicalin combined with matrine can enhance the inhibitory effect on lipo-polysaccharide-induced pneumonia in mice [17]. Another report shows that baicalin can inhibit influenza virus, reduce the virus titer in rats after treatment, and decrease death rate from the infection [23].

 

The other main component of Scutellaria is baicalein. It can inhibit interleukin-mediated inflammation [18]. Allergic reactions caused by viral pneumonia aggravate inflammatory exudation, and baicalein can inhibit systemic allergic reactions by inhibiting the release of inflammatory mediators and degranulation of mast cells [19, 20]. Severe COVID-19 can cause acute respiratory distress syndrome (ARDS), which leads to refractory noncardiogenic pulmonary edema and pulmonary hypertension [21]. Baicalein can improve on monocrotaline-induced rat pulmonary hypertension by inhibiting vascular remodeling. The mechanism of pulmonary hypertension may be related to its inhibition of mitogen-activated protein kinase and NF-κB signaling pathway [22].

Most exciting discovery was done recently by Su H. et al[3]. They have stated it eloquently: "Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs."  Bravo!

REFERENCES

[12] An X, Gong Y, Ye L, Jin M. Advance on studies of T helper 17 cells and its relative cytokines and bronchial asthma. Int J Respir, 2012,32(1):43-46.

[13] 王平. 黄芩苷对过敏性哮喘小鼠Th17/Treg 反应失衡的调节作用研究[D]. 吉林延边大学,2016.

[14] Chao H, Tang G, Wan Y. Baicalin has effects of prevention and cure on rats with chronic obstructive pulmonary disease by regulating IFN-γ. Int J Respir 2012,32 (1):18-21.

[15] Xu Z,Shi L,Wang YJ,et al. Pathological findings of COVID -19 associated with acute respiratory distress syndrome [J/OL ]. Lancet Respir Med, 2020,doi :10. 1016/S2213-2600(20 )30076-X.

[16] Bai L, Yang Y, Wan Q. Baicalin alleviated rheumatoid arthritis synovitis of SD rats through TLR2-NF-κB pathway.  Chinese Pharmacological Bulletin 2017,33(11):1569-1573.

[17] Wang F, Sun Y, Yin W, Fan K, Duan Z, Sun N, Li H.  Effects of matrine combined with baicalin on mouse pneumonia induced by LPS.  Chinese Pharmacological Bulletin 2018,34 (8):105-109.

[18] Dubravko J,Lower-Nedza AD,Brantner AH,et al. Baicalin and baicalein inhibit arc tyrosine kinase and production of IL-6 [J ]. J Chemistry, 2016 :2510621.

[19] Bae MJ,Shin HS,See HJ,et al. Baicalein induces CD4+ Foxp3+ T cells and enhances intestinal barrier function in a mouse model of food allergy[J]. Sci Rep,2016,6 :32225.

[20] 板本首正. 黄芩中黄芩素剂色苷酸二钠对肥大细胞脱颗 粒的抑制效果[J]. 国外医学院中医中药分册,1984,7(2):52.

[21] Ñamendys-Silva, S.A.; Santos-Martínez, L.E,Pulido T,et al. Pulmonary hypertension due to acute re-

spiratory distress syndrome [J ]. Braz J Med Biol Res. 2014,47(10):904-910.

[22] 魏泽卉. 黄芩素通过抑制血管重构改善野百合碱诱导的 大鼠肺动脉高压[D]. 太原院山西医科大学,2017.

Oregano Oil

We have chosen the highest quality of oregano oil, containing 86% of carvacrol and thymol. Numerous studies have shown that these two components have anti-bacterial, anti-fungal, and a wide range of anti-inflammatory and anti-oxidant activity, and are safe and non-toxic [41]. In vitro studies of human lung cells found that thyme extract (which, like oregano oil, contains thymol and carvacrol) inhibits muc5ac factor related to mucus secretion, thus it is recommended for addressing the inflammation of respiratory system linked to secretory fluid. [42].  In patients with severe viral pneumonia, difficulty to cough effectively and expel sputum, partly caused by weakened cilia motor function, will worsen the disease.  Thyme extract not only has anti-inflammatory effects, but also increases the frequency of cilia movement [43]. In addition, thyme extract can combat endothelin-induced bronchospasm and allow more oxygen to enter the alveoli [44].

In recent years, the potential antiviral value of thymol and carvacrol and their unique effects on biofilms have attracted attention. In vitro experiments have shown that norovirus that infect mice have a coat protein size of ≤35 nm. After 1 hour of thymol treatment, it can be Increased to 800 nm and lost its integrity. Thymol then significantly inhibited the virus survival [45]. Thymol has inhibitory effects on a variety of viruses such as respiratory syncytial virus, herpes virus, and digestive tract rotavirus [46] ]. In 2003, during  SARS epidemic, it was found in human cell experiments that thymol alone or in combination with monoterpenoids can inhibit SARS-CoV proliferation [47]. Thymol, carvacrol, and other volatile phenols have small molecular weights and an average mass of 150.218 Da.  Being lipophilic it has affinity with fatty acids on biofilms, and can destroy ion pumps on cell membranes, affect sodium-potassium exchange and depolarization processes, and damage mitochondrial ATP energy transfer, destroying the cell structure and causing death of bacteria or molds [48,49]. Electron microscopy shows that thymol can destroy the herpes virus envelope to achieve antiviral purposes, which is different from the mechanism of acyclovir, even for acyclovir resistant herpes virus, thymol can still reduce the virus titer of 95.6% ~ 99.6% [50]. It is postulated that this feature of thymol may synergize with other antiviral drugs to achieve better antivirus effect.

REFERENCES

[41] Sienkiewicz M,Lysakowska M,Denys P,et al. The antimicrobial activity of thyme essential oil against multidrug resistant clinical bacterial strains[J]. Microb Drug Resist,2012,18(2):137-148.

[42] Oliviero M,Romilde I,Beatrice MM,et al. Evaluations of thyme extract effects in human normal bronchial and tracheal epithelial cell lines and in human lung cancer cell line[J ]. Chem Biol Interact,2016,256 :125-133.

[43] Nabissi M,Marinelli O,Morelli MB,et al. Thyme extract increases mucociliary-beating frequency in primary cell lines from chronic obstructive pulmonary disease patients [J]. Biomed Pharmacother, 2018,105 :1248-1253.

[44] Engelbertz J,Schwenk T,Kinzinger U,et al. Thyme extract, but not thymol, inhibits endothelin-induced contractions of isolated rat trachea [J]. Planta Med,2008,74(12):1436-1440.

[45] Gilling DH,Kitajima M,Torrey JR,et al. Antiviral efficacy and mechanisms of action of oregano essential oil and its primary component carvacrol against murine norovirus [J ]. J Appl Microbiol, 2014,116(5):1149-1163.

[46] Pilau MR,Alves SH,Weiblen R,et al. Antiviral activity of the Lippia graveolens (Mexican oregano) essential oil and its main compound carvacrol against human and animal viruses [J ]. Braz J Microbiol,2011,42(4):1616-1624.

[47] Erik Goldman. Oregano oil proves effective against coronavirus [EB/OL ]. https ://www. holisticprimarycare. net/topics/topics-h-n/infectious-disease/117-oregano-oil-proves-effective-against-coronavirus. html,2009-12-01.

[48] Di Pasqua R,Hoskins N,Betts G,et al. Changes in membrane fatty acids composition of microbial cells induced by addiction of thymol, carvacrol, limonene, cinnamaldehyde, and eugenol in the growing media[J]. J Agric Food Chem,2006,54

(7):2745-2749.

[49] Gucwa K,Milewski S,Dymerski T,et al. Investigation of the antifungal activity and mode of action of Thymus vulgaris,Citrus limonum,Pelargonium graveolens,Cinnamomum cassia,Ocimum basilicum,and Eugenia caryophyllus Essential Oils[J]. Moleciles,2018,23(5):1116.

[50] Schnitzler P,Koch C,Reichling J. Susceptibility of drug-resistant clinical herpes simplex virus type 1 strains to essential oils of ginger,thyme,hyssop,and sandalwood[J]. Antimicrob Agents Chemother,2007,51(5):1859-1862.

Peppermint Oil

Peppermint oil is obtained by steam distillation from the fresh aerial parts of the flowering plant of Mentha × piperita L. (aka peppermint). Menthol is an active ingredient of peppermint. The therapeutic use of peppermint oil includes the symptomatic treatment of coughs and colds [1]. When inhaled, it creates a cooling sensation that can soothe or numb a scratchy throat. This may also explain why peppermint oil can ease breathing in people with allergy or inflammation. One study also shows that peppermint oil can relax bronchial smooth muscles, increase ventilation and brain oxygen concentration, and decrease blood lactate level [2].

The expectorant action of peppermint oil can help clear symptoms of upper respiratory congestion that may stem from allergies, asthma, bronchitis, cold, flu, and the like. In an Israel study, a spray using aromatic essential oils, including peppermint oil, was administered. It was concluded that the spray application brought immediate and significant improvement in upper respiratory health[3].

REFERENCES

[1] Györgyi Horváth, Kamilla Ács, Essential oils in the treatment of respiratory tract diseases highlighting their role in bacterial infections and their anti‐inflammatory action: a review, , Flavour and fragrance J.:26 May 2015

[2] Abbas Meamarbashi1 and Ali Rajabi1, The effects of peppermint on exercise performance, J Int Soc Sports Nutr. 2013; 10: 15.

[3] Ben-Arye E, Dudai N, Eini A, Torem M, Schiff E, Rakover Y. Treatment of upper respiratory tract infections in primary care: a randomized study using aromatic herbs. Evid Based Complement Alternat Med. 2011;2011:690346. doi: 10.1155/2011/690346. Epub 2010 Nov 1.

 

 

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