The UK Phyto-V Study
Ethics number: IRAS (Ethics) Number: 282517. EudraCT number: 2020-001532-10
MHRA – non-drug notification May 2020
Summary: This is potentially the World’s largest nutritional intervention study involving men and women with symptomatic covid-19 infection. It is trying to establish whether boosting the diet with natural phytochemical rich concentrated foods, in addition to a specifically designed, safe, lactobacillus probiotic and prebiotic could reduce the severity of symptoms, improve gut health, speed up recovery and prevent late complications of a covid-19 infection.
It has been designed and conducted from Bedfordshire Hospitals Lifestyle Research Unit, UK by a team of nutritionalist, chest physicians, oncologist, research pharmacist, A&E consultants and scientists. It aims to recruit 135 participants from from across the UK in the most robust scientific design – a double blind randomised design.
Now recruiting – your help is really needed
Please email the trials lead (email@example.com) if you have had covid and still have symptoms. You can be sent more information and if happy consented over the phone. You will be sent the probiotics and trial food capsules. There are no extra blood tests, investigations or visits to the hospital – you just have to answer some questions about your symptoms at the start and after one month.
A randomised double blind placebo controlled trial evaluating the influence of phytochemical rich foods capsule in addition to a probiotic capsule on clinical outcomes amoung individuals with covid-19 viral infection
(The UK Phyto-V Study)
Background and rationale
On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the world, and on the 11th of March, the WHO declared that COVID-19 was a pandemic. Covid-19 is an enveloped, positive-sense single-stranded RNA (ssRNA) virus belonging to the Coronaviridae family. The CoV family consists of several species and causes upper respiratory tract and gastrointestinal infections in mammals, bats and birds. In humans, it mainly causes common cold, but complications include pneumonia.
There are no specific treatments for CoV infection and acute management is entirely supportive. Preventive vaccines are still being explored. Exiting antiviral drugs administered shortly after symptom onset have only marginal benefits in reducing infectiousness to others by lowering viral shedding in the respiratory secretions of patients (SARS-CoV-2) but their routine use is not current policy [Welliver]. In the current pandemic, most cases recover fully but about 20% require hospital treatments and 10% intensive care of which 50%.Progress of the disease, is linked with a consequent release of pro-inflammatory such as IL-6 and TNF-α cytokines. A serious complication of SARS-CoV infection is the sudden development of excessive inflammatory pulmonary infiltrates which causes severe respiratory distress, this has been terms a cytokine storm. A great deal of effort has been devoted to targeting the host response with a variety of anti-inflammatory drugs including treatment with corticosteroids, aspirin, monoclonal antibodies (MAbs), anti-cytokine and anti-chemokine agents, plasma exchange, and statins. Unfortunately, none has been proved to be effective [Meijvis], and some with sensitivities to salicylates or similar drugs have worsened the outcome [Tisoncik, Lo]. Ongoing studies are evaluating the immunomodulatory effect of hydroxychloroquine in controlling the cytokine storm and as mentioned above, trials are ongoing [Yoa]. Clinical trials of hydroxychloroquine treatment for COVID-19 pneumonia are ongoing (NCT04261517 and NCT04307693). Studies have also shown that superoxide anion produced by macrophages infiltrated into the virus-infected organs is implicated in the development of severe influenza-associated complications.
Why one person gets a severe infection and other not is not entirely understood and genetic variabilities in both the host and virus are likely to be important [Wu]. Data collected from hospitals across the World showed that people with pre-existing health conditions or who are overweight are more vulnerable to catching covid-19 infection, developing the complications of infection. One possible explanation for this is a pre-existing poor gut health or dietary habits which could lead to a pro-inflammatory state. Pre-existing chronic conditions which weaken cardiac or pulmonary function reserve have an influence on whether an effective individual is able to sustain the viral insult. There is a suggestion that polyphenols could enhance intracellular oxidative enzyme capacity can help scavenge excess superoxide anions [Uchide].
Phytochemicals, especially the polyphenol groups are naturally responsible for the colour, taste and aroma of foods. Their regular intake in fruits, herbs and vegetables has been linked with multiple health benefits particularly reducing chronic degenerative disease and reducing excess chronic inflammation [Thomas,Powanada, Bailey, Thomas, Thomas]. Numerous laboratory experiments have shown they favourably effect multiple biological pathways in the body, can indirectly via enhancing bacterial gut health, especially if combined with probiotic bacteria and are reported to have direct anti-viral properties [Chaing, Li, Lin, Ge, Wu, Lau, Yu]. If these benefits are extrapolated to humans, boosting their intake could potentially reduce the chance of catching the virus, suffering from their adverse effects or spreading it to other people.
Potential beneficial mechanism of phytochemical and probiotic rich foods
Improving gut health: Some polyphenols such as plant lignans found in nuts, resveratrol in red wine, ellagitannin found in tea as well as celery, pomegranate and turmeric act as prebiotics to healthy bacteria which improve gut health and integrity which reduces the absorption of proinflammatory toxins into the systemic circulation [Powanda]. Laboratory and clinical studies have shown that increased toxin exposure due to poor gut health can lead to immune and inflammatory disfunction [Shen]. Studies in the elderly have shown that enhancing the diet with a probiotic supplement could help reduce age related falls in natural killer cell activity [Gill].
Probiotics are live microorganisms, which when administered in adequate amounts confer a health benefit on the host [WHO]. Microbes used as probiotics are derived from different genera and species and have been studied extensively for a variety of health and disease endpoints. The most commonly used, naturally occurring bacteria used as probiotics, which work particularly well if given with certain prebiotic gut health enhancing bacteria which then grow, out spacing proinflammatory (Firmicutes). A study from Australia gave healthy athletes either prebiotic and probiotics or placebo. After one year the probiotic group had less colds and as a consequence had less disruption to their training. Athletes in Australia and across the world now take probiotics regularly. Several studies have shown that regular intake of live lactobacilli, shortened the duration and severity of upper respiratory tract infections [Fujita, Rerksuppaphol]. In 2011, a summary of all international studies was published in the prestigious Cochrane Database of Systematic Reviews, and concluded that probiotics also reduced the incidence of upper respiratory tract infections [Hoa].
Reducing excess inflammation: Fresh vegetables, fruit, herbs and spices have been shown to reduce COX–2 activation of prostaglandins via modulation of the function of NF‐κB, [Blacklock, Zakkar]. Polyphenols in turmeric and celery can dampens down excess inflammation via de-activation of NF-kappaB which could overwise increases chemokines, cyclooxygenase 2 and RANK levels [Handler, Thomas]. Consistent with these findings, tissue inflammatory cell influx, have been shown to be inhibited by turmeric extract supplementation [Funk].Likewise they have been shown to reduce inflammatory associated pain in joints [Powanada, powdnada]. Yet unlike aspirin, ibuprofen, which can damage the gastric mucosa, polyphenol rich foods have been shown to protect it [Al-howiriny].
Reducing excess oxidative stress: As well as reducing inflammation, polyphenols can help reduce excess oxidative stress within tissues. Their antioxidant enhancing properties stem from an ability facilitate activation of the transcription factor NF‐E2–related factor 2 (Nrf2), which enhances an appropriate antioxidant response to damaging reactive oxidative species [Stivala, Davidosn, Juge, Dinkova‐Kostova). ROS are generated at higher levels in obesity, after eating unhealthy foods such as burnt meat and processes sugar or disease such as diabetes and obesity (Wang, Marseglia). Polyphenols also promote the natural adaptive to ROS during exercise yet do not affect the degradation of antioxidant enzymes after exercise so the time cells spend with optimal oxidative balance is greatly extended [Poljsak, Ristow, Eder, Teixeira, Avery, Peternelj, Lotito]. There is a suggestion that polyphenols could enhance intracellular oxidative enzyme capacity can help scavenge excess superoxide anions and potentially help red [Uchide].
Although some phytochemicals could have weak direct anti-oxidant properties, in the past, this aspect has been overstated. In fact, many people previously referred to them only as anti-oxidants which is misleading and diminishes the importance of their, other biochemical properties. Unlike direct anti-oxidant vitamins A & E (highlighted below), they do not over deplete ROS levels causing anti-oxidative stress, instead they improve antioxidant efficiency and capacity when needed.
Tissue oxygenation: Polyphenol rich foods such as celery, pomegranate, beetroot and other leafy green vegetables are rich in nitrates which, in the presence of vitamin C and polyphenols, are converted to nitric oxide (NO) [Lundberg].These have been shown to help to improve muscle oxygenation, increase the time to fatigue [Bailey, Bondon, D’Angelo].
Anti-viral potential of polyphenol rich foods: Numerous in vitro experiments have demonstrated significant anti-viral properties of phytochemical rich plants including SARS-associated coronavirus [Li, Lin, Ge, Wu, Lau, Yu]. Clinical studies are lacking which many believe is due to the difficulties and cost of human studies using plants which cannot be intellectually protected commercial so are of little interest to big pharma [Kotwal]. Furthermore, as foods have multiple different phytochemicals, vitamins, minerals, prebiotic fibres its more difficult to establish whether it’s one candidate polyphenol or a combination of all which provides the therapeutic effect [Lin].
Developing the nutritional intervention for the Phyto-V study
It is important to emphasise a well-balanced diet rich in fruit vegetables, herbs and spices but concentrating certain polyphenol rich whole foods into a supplements is a convenient way to boost their intake especially among individuals who may not have particularly varied diet or have a poor appetite. Although they are safe, very unlikely to do harm, they may to financial burden on families and their popularity remains strong so its important to collect robust evidence of their potential benefits [Thomas K].
The phytochemicals particularly the 6 polyphenol group, which show promise and are found in common foods include: The flavanone polyphenol hesperetin found in citrus fruits; the anthraquinone derivative aloe emodin found in Aloe Vera; Quertin, a flavonoid found in, onions, apple, pomegranate and citrus fruits;Apigenin a polyphenol found in parsley, chamomile, tea and fruit; curcumin curcuminoids found in turmeric; ellagic acid found in pomegranate. Rational for their inclusion in this supplement are now explained further:
Ellagic Acid and Epigallocatechin-3-gallate (Pomegranate, tea, red wine): Pomegranate, particularly the ground seeds are rich in anthocyanins, flavonoids, gallic acid, ellagic acid, quercetin, and ellagitannins. In a laboratory study the antiviral (HRV) property and mechanism of action of ellagic acid were evaluated measuring real-time reverse transcription-PCR levels using HeLa cells. The 50% inhibitory effect on RNA replication of natural ellagic acid was twice that of ribavirin. It also mainly protected cells after viral inoculation virus inoculation which the authors suggested that ellagic acid inhibits virus replication by targeting on cellular molecules, rather than virus molecules [Park]. Similar in vitro experiments have demonstrated similar findings for pomegranate and tea polyphenols, ellagic acid epigallocatechin-3-gallate in extracts and whole foods, in hepatitis C infected cells [Calland], HIV, influenza A and B infected cells both by slowing viral replication and reducing penetration through the cell wall [Neu, Su, Sundararajan, Yang].
Curcuminoids (Turmeric): circumoids has been identified as a potential inhibitor of hepatitis C virus replication, potentially by competitively suppressing sterol regulatory element binding protein pathways [Kim] and more recently its negative effect on HCV cell penetration has been demonstrated [Anggakusuma]. Other studies have shown curcumin to inhibit proliferation of Human Papilloma virus [Maher] as well as parainfluenza virus type 3 (PIV-3), feline infectious peritonitis virus (FIPV), vesicular stomatitis virus (VSV), herpes simplex virus (HSV), flock house virus (FHV), and respiratory syncytial virus (RSV), VSV and FIPV/FHV [Jassim]. What’s more a study demonstrated considerable synergy between curcuminoids and ellagic acid in pomegranate and tea in their ability to generate ROS mediated apoptosis in HPV infected HeLa cells The combination of Curcumin and Ellagic acid at various concentrations showed better effects than either of the foods when used alone. [Kumar]
Apigenin ( Chamomile, parsley, celery, citrus fruits) rich foods have demonstrated many health benefit including [Aherne, Shulka,]. It is a particularly commonly consumed drink in Germany, consumed as single ingredient chamomille tea is, prepared from the dried flowers from Matricaria chamomilla [McKay] In terms of viral effects, apigenin extracts have shown to induce anti-HIV activity in T-cell lines transfected with HIV-I and HIV-1 (IIIB) infected MT-4 cells, respectively, by integrase inhibitory activity [Tang, Lee, Critchfield]. Apigenin has been shown to slow viral replication by suppressing internal ribosomal entry site (IRES) mediated translational activity and by modulating cellular c-Jun N-terminal kinase (JNK) pathways [Lv, Qian].
Quercetin (Onions, pomegranate, citrus fruit): Quercetin displayed antiviral activity against different influenza virus strains, including H1N1and H3N2 [Song]. The inhibitory effect of quercetin was particularly enhanced when the virus was pre-incubated with quercetin, or the cell was infected with the virus in the presence of quercetin. This suggested that quercetin could inhibited virus infection and cell entry and reduced complications associated with the (H1N1) virus infection [Wu].
Hesperetin (Citrous fruit). Citrus fruits an some vegetables contain several naturally occurring dietary bioflavonoids including hesperetin, naringin, and catechin which have demonstrated inhibitory effects on various viruses including herpes simplex virus type 1 (HSV-1), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) in different mechanisms. Hesperetin had no effect on infectivity but it reduced intracellular replication [Lin]. Catechin inhibited the infectivity but not the replication [Kaul, Mycol]. Oxidation of citrus is important because it breaks down the hesperetin skeleton which has been shown to decrease its antiviral activity [Paredes]. Some bioflavonoids have demonstrated specific replication inhibition effects on SARS-CoV infected cells [Ryu].
Aloe Emodin (Aloe Vera). Aloe vera is an evergreen herbaceous plant widely grown in the tropical and subtropical regions. A. vera contains a large amount of bioactive ingredients, such as vitamins, amino acids, trace elements, polysaccharides, and anthraquinones; as such, it has antibacterial, anti-inflammatory, antioxidant, wound healing-promoting, and immunity-enhancing functions [Radha, Yagi]. The anthraquinone derivative aloe-emodin reported anti-proliferative effects particularly against the highly pathogenic H5N1 virus responsible for the last pandemic in 2013. The mechanism of action of anthraquinones appears to be in its inhibiting of replication by via galectin-3 up-regulation which in turn reduces RNA-dependent protein kinase and 2’5′,-oligoadenylate synthetase expression. [Sun, Lin, Li 2014]. A. vera has also shows antiviral activity herpes simplex virus [Syed], Human papillomavirus infection [Iljazovic] human immunodeficiency virus [Kahlon, Radha] and has been approved by the US FDA as an adjuvant for the treatment of AIDS in humans.
Manufacturing, safety and quality assurance
The phytochemical rich foods supplement and probiotics and placebo have been made specifically for this trial by one of the more established UK manufacturers. Both have been certified FSSC 22000 (ISO 22000) and all operations confirm to Good Manufacturing Practice (GMP), UK and International law [www.tohc.co.uk]. They are also certified Organic by the Organic Food Federation. They have an inhouse Research and Development which measure and confirm the quality and polyphenol content of each batch for this study. Every batch is also tested for biological contamination, TBC, yeast, mould, E.Coli and Salmonella for safety. They also measure, Lead, Arsenic, Cadmium, Mercury and pesticides abiding by international threshold guidance and law.
There is considerable interest in probiotics for a variety of medical conditions, and millions of people around the world consume probiotics daily for perceived health benefits. There are rare instances of excess bacterial overgrowth with prolonged excessing use and diarrhoea with especially E.coli [Rao] but the risk of adverse effects with Lactobacillus use was estimated in a French study to be at about one case per 10 million people over a century of probiotic consumption [Bernardeau]. Moreover, the risk of lactobacillemia was considered as ‘unequivocally negligible’, at <1 case per million individuals [Borriello]. Further evidence for safety was derived from a retrospective study that showed that increased probiotic consumption of Lactobacillus rhamnosus GG in Finland did not lead to increased cases of Lactobacillus bacteremia [Salminen] Furthermore, clinical studies where certain probiotics have been safely administered to immunocompromised patients (for example, patients with HIV infection), premature infants, elderly and patients with Crohn’s disease without any side-effects provide further evidence of poor opportunistic pathogenicity [Bernardeau 2008].
Large quantities of probiotics consumed around the world, the numbers of opportunistic infections that result from probiotic supplements are negligible. For example, probiotics have been administered to thousands of new born infants, including some who were premature without a single case of sepsis [AlFaleh]. They have been used in trials involving patients severely ill in intensive care and a recent meta-analysis of 13 RCT involving potentially immunocompromised patients on chemotherapy reported a significant reduction in diarrhoea and an improvement in other symptom [NIH]. For these reasons, the common probiotic species such the Lactobacillus used in this trial are very unlikely to cause harm and this is support by many international academic bodies [World, Gibson].
There has never been a statistically valid study, which has shown that polyphenol rich foods cause harm – and that applies to whole foods or dried concentrated versions in capsules [Thomas, Thomas]. The supplement used in study is using foods at quantities which can obtained from diet. They are concentrated using techniques which removes the sugar, water and fibre yet concentrates the natural polyphenols [Aggarwal].
No Vitamin A, E or direct anti-oxidants – It is very important to differentiate polyphenol rich whole food supplements with direct antioxidant chemical extracts such as Vitamins A and E. They have very different properties and risks yet they are often grouped together as “supplements”, “vitamins” or “antioxidants” in the media [Sayin, Le Gal]. Polyphenols promote a natural adaptive increase in anti-oxidant enzymes [Stivala, Davidson, Juge,], unlike direct antioxidants such as vitamin A and E which can actually block this process so can increase oxidative damage leading to increase impede tissue repair [Teixeira, Avery, Poljsak, Eder, Ristow, Gomez-Cabera, Peternelj]. Polyphenols also enhance an enzyme called keap 1 which signals nrf2 to reduce the anti-oxidant levels when the oxidative environment diminished. Vitamin A & E anti-oxidants which have the opposite [Eder, Ristow]. Combined with their ability to neutralize ROS by directly donating a hydrogen atom this can result in the mopping up of too many ROS that can lead to a state called anti-oxidative stress [Poljsak]. This can also cause tissue damage as our cells do need a certain level of ROS for normal functions such as regulating vascular tone, monitoring of oxygen tension and normal response to pathogen attack [Poljsak, Ristow, Schulz, Son].
In terms of cancer, numerous cohort studies linked higher intake of polyphenol rich foods with a lower cancer risk and lower risk of relapse [Wang, Bradbury, Block, Buck]. The UK Pomi-T randomised controlled study which evaluated a capsule containing dried whole polyphenol rich foods (turmeric, green tea, broccoli and pomegranate) reported a statistically significant effect on markers of progression in men with early prostate cancer [Thomas, Thomas].
Turmeric is recognized as safe by the FDA as a food additive. Serious adverse effects have not been reported in humans, even in those taking high doses of curcumin. A dose escalation trial in 24 adults found that single oral dosages up to 12g were safe, and adverse effects were not dose-related [Lao]. In a phase I trial in Taiwan, curcumin supplementation up to 8g/day for three months was reported to be well-tolerated [Cheng]. In another clinical trial in the UK, curcumin supplementation ranging from 0.45-3.6 g/day for four months was generally well-tolerated by people with advanced colorectal cancer, although two participants experienced diarrhoea and another reported nausea [Sharama]. There is no evidence that dietary consumption of turmeric as a spice adversely affects pregnancy or lactation, although the safety of curcumin supplements in pregnancy and lactation has not been established. Curcumin has been found to inhibit platelet aggregation in vitro [Shah], suggesting a potential for curcumin supplementation to increase the risk of bleeding in people taking anti-platelet medications, but no reports have been documented in humans. Clinical studies have reported minimal or no adverse events even with intake over 3g/day [Thomas, Shah, Sharma, Loa].
Pomegranate fruit, the juice or it’s dried concentrated extracts have no safety issues reported for pomegranate juice extract apart from rare food allergies. The Johns Hopkins study above reported a 14% of diarrhoea if doses were over 3g a day, but only 2% if below this dose. There are some potential drug inactions because like many fruit juices, pomegranate is a weak inhibitor of cytochrome P450 (CYP2C9). There is, therefore, a small potential risk of reducing the metabolism, and thereby increasing serum levels of warfarin and other coumadins, anti-hypertensives such as captopril, ramipril or anti-convulsants such a carbimazole (www.rxlist.com). Men on warfarin had no interference of their INR or blood pressure in a previous similar study [Thomas].
Within the low concentrations used in this interventions the risk of toxicities from Aloe vera extract are very small, especially for a short intervention but could include diarrhoea [Guo]. Chamomile and citrus are particularly safe and they consumed by millions for people every day.
Trial Design and methodology
This is a double blind placebo controlled randomised trial run from the research unit at Bedford Hospital. Participants are given a written information sheet explaining the details via email. On day 2, if the patients subsequently agrees to enter the study, via a telephone consultation, he/she will be randomised to either a phytochemical rich food supplement containing extracts of several phytochemical rich foods or placebo (1:1 randomisation). In addition they will be given a capsule containing a lactobacillus probiotic bacterial blend. The probiotic arm of the trial is not blinded and these have been donated to the study by YourGut+ . These will be delivered to all participants, in boxes containing 60 tablets.
During these telephone consultations the trials team will discuss healthy living advice such as exercising regularly out doors in the fresh air. Participants will be telephoned a regular intervals by the trials nurse who will annotate the body temperature taken by the participant themselves ( if they do have a thermometer, one will be sent them). The trials nurse will complete a formal cough scale, a Subjective wellness score, a formal fatigue score and record any symptoms using the NCI common toxicity checklist. The nurse will also speak to the other household members who have consented to enter the study, if they have developed any symptoms and invite them to enter the study
End points: The primary end point will be time to recovery from start of the study in terms of pyrexia, cough or any other relevant symptom. The secondary patient end points will whether in-patient or intensive care was required or whether house hold members because symptomatic.
Acknowledgements: The scientific committee are very grateful to the designers and manufacture’s of Yourgut+ for suppling this probiotic free of charge for this study.
Al Faleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014:Cd005496
Aherne SA, O’Brien NM. Dietary flavonols: chemistry, food content and metabolism. Nutrition. 2002;18:75–81.
Anggakusuma, Colpitts CC, Schang LM, et al. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut. 2013 Gut. 2014 Jul;63(7):1137-49
Avery NG, Kaiser JL, Sharman MJ et al Effects of vitamin E supplementation on recovery from repeated bouts of resistance exercise. J Strength Cond Res. 2003 Nov;17(4):801-9.
Berggren A, Lazou Ahren I, Larsson N, Onning G. Randomised, double‐blind and placebo‐controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. European Journal of Nutrition 2010 Aug 28
Bernardeau M, Vernoux JP, Henri-Dubernet S, Gueguen M. Safety assessment of dairy microorganisms: the Lactobacillus genus. Int J Food Microbiol. 2008;126:278–285.
Bernardeau M, Guguen M, Vernoux JP. Beneficial lactobacilli in food and feed: long-term use, biodiversity and proposals for specific and realistic safety assessments. FEMS Microbiol Rev. 2006;30:487–513.
Block G, Patterson B, Subar A (1992) Fruit vegetables and cancer prevention a review of the epidemiological evidence. Nutr Cancer 18: 1-29.
Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003;36:775–780.
Bradbury KE, Appleby PN, Key TJ (2014) Fruit, vegetable and fiber intake in relation to cancer risk findings from the European Prospective investigation into Cancer and Nutrition (EPIC). Am J Clin Nutr 100: 394-398.
Calland N, Albecka A, Belouzard S, Wychowski C, Duverlie G, Descamps V, et al. (-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology. 2012;55:720–9.
Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895-2900.
Choi C, Kim JK, Choi SH, et al. Identification of steroid hormones in pomegranate (Punica granatum) using HPLC and GC mass spectrometry. Food Chemistry 2006; 96: 562–571.
Critchfield JW, Butera ST and Folks TM. Inhibition of HIV Activation in Latently Infected Cells by Flavonoid Compounds. AIDS Research and Human Retroviruses 1996, 12, 39–46Davies KJ. Oxidative stress: the paradox of aerobic life.Biochem Soc Symp. 1995; 61():1-31.
Doron S, Snydman DR Risk and safety of probiotics.. Clin Infect Dis. 2015,15; 60 Suppl 2:S129-34.
Fujita R, Iimuro S, Shinozaki T, et al. Decreased duration of acute upper respiratory tract infections with daily intake of fermented milk: a multicenter, double‐blinded, randomized comparative study in users of day care facilities for the elderly population. American Journal of Infection Control 2013;41(12):1231‐5.
Ge H, Wang YF, Xu J, Anti-influenza agents from Traditional Chinese Medicine.Nat Prod Rep. 2010; 27(12):1758-80.
Gill HS, Rutherfurd KJ, Cross ML. Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes. J Clin Immunol. 2001;21:264–271.
Gibson GR, Hutkins R, Sanders et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017;14:491-502.
Guo X, Mei N et al. Aloe vera: A review of toxicity and adverse clinical effectsJ Environ Sci Health C Environ Carcinog Ecotoxicol 2019; 2; 34(2): 77–96
Hao Q, Dong B, Wu T et al Probiotics for preventing acute upper respiratory tract infections: A cochrane metanalysis (2015) https://doi.org/10.1002/14651858.CD006895.pub3
Hu F, Wang YB, Liang J, et al: Carotenoids and breast Cancer risk: a meta-analysis and meta-regression. Breast Cancer Res Treat 131(1):239-253, 2012
Iljazovic E, Zulcic-Nakic V, Latifagic A, Sahimpasic A, Omeragic F and Avdic S. (2006). 245 ORAL Efficacy in treatment of cervical HRHPV infection by combination of interferon, Aloe vera and propolis gel associated with different cervical lesion. Eur. J. Surg. Oncol. 32 S73–S139. 10.1016/S0748-7983(06)70680-1.
Jassim SAA, Naji MA. Novel antiviral agents: a medicinal plant perspective. Journal of Applied Microbiology. 2003;95(3):412–427. [PubMed] [Google Scholar]
Kahlon J., Kemp M., Carpenter R., McAnalley B., McDaniel H., Shannon W. (1991a). Inhibition of AIDS virus replication by acemannan in vitro. Mol. Biother. 3 127–135.
Kaul TN, Middleton E Jr, Ogra P et al Antiviral effect of flavonoids on human viruses. J Med Virol. 1985, 15(1):71-9.
Kotwal G. Natural anti-virals against human viruses, Virol Mycol 2014, 3:2 DOI: 10.4172/2161-0517.1000e107
Kim K, Kim KH, Kim HY, et al . Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway. FEBS Lett. 2010;584:707–12.
Kumar D, Basu S, Parija L et al Curcumin and Ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells.Biomed Pharmacother. 2016;81:31-37. doi: 10.1016/j.biopha.2016.03.037.
Lao CD, Ruffin MT 4th, Normolle D. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006 Mar 17;6:10.
Lau KM, Lee KM, Koon CM, Cheung CS, Lau CP, Ho HM, et al. Immunomodulatory and anti-SARS activities of Houttuynia cordata. J Ethnopharmacol. 2008;118:79–85.
Lee JS, Kim HJ and Lee YS. A New Anti-HIV Flavonoid Glucuronide from Chrysanthemum Morifolium. Planta Medica 2003, 69, 859–861
Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antivir Res. 2005;67:18–23
Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, et al. Anti-SARS coronavirus 3C-like protease effects of plant-derived phenolic compounds. Antivir Res. 2005;68:36–42.
Lin L, Hsu W, Lin C, et al Antiviral Natural Products and Herbal MedicinesJ Tradit Complement Med. 2014 Jan-Mar; 4(1): 24–35. doi: 10.4103/2225-4110.124335
Lin CW, Tsai FJ, Tsai CHAnti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res. 2005 Oct;68(1):36-42.
Li S, Yang T, Lai C et al Antiviral activity of aloe-emodin against influenza A virus via galectin-3 up-regulation. Eur J Pharmacol. 2014 Sep 5;738:125-32. doi: 10.1016/j.ejphar.2014.05.028..
Lo P, Tsai Y, Lin S, et al Risk of asthma exacerbation associated with nonsteroidal anti-inflammatory drugs in childhood asthma: A nationwide population-based cohort study Medicine (Baltimore) 2016 ; 95(41).
Lu D et al Probiotics in preventing and treating chemotherapy-induced diarrhea: a meta-analysis of 13 RCT.Asia Pac J Clin Nutr. 2019;28(4):701-710. doi: 10.6133/apjcn.201912_28(4).0005.
Lv, X.; Qiu, M.; Chen, D, et al. Apigenin Inhibits Enterovirus 71 Replication Through Suppressing Viral IRES Activity and Modulating Cellular JNK Pathway. Antiviral Research 2014, 109, 30–41.
McKay DL, Blumberg JB. A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.) Phytother Res. 2006;20:519–530. [PubMed] [Google Scholar]
Maher DM, Bell MC, O’Donnell EA et al Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV E7. Mol Carcinog. 2011; 50(1):47-57.
Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jun 11; 377(9782):2023-30.
Mycol V, Kotwal GJ and Longum P. Natural Antivirals against Human Viruses with Bitter melon. Virol. Mycol. 2014;3:3–5.[Google Scholar] [Ref list]
National Institute of Health – Probiotics fact sheet for professionals https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/
Neurath AR, Strick N, Li YY, Debnath AK (2004) Punicagranatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. BMC Infect Dis 4: 41.
Paredes A1, Alzuru M, Mendez J et al Anti-Sindbis activity of flavanones hesperetin and naringenin. Biol Pharm Bull. 2003;26(1):108-9.
Park S, Hwon M, Yoo J et al Antiviral activity and possible mode of action of ellagic acid identified in Lagerstroemia speciosa leaves toward human rhinoviruses. BMC Complement Altern Med. 2014; 26;14:171. doi: 10.1186/1472-6882-14-171.
Peternelj TT, & Coombes JS (2011). Antioxidant Supplementation during Exercise Training: Beneficial or Detrimental? Sports medicine (Auckland, N.Z.), 41 (12), 1043-69.
Pierce JP, Natarajan L, Caan BJ, , et al. (2007) Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer the Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA 298: 289-298.
Pierce, J. P., L. Natarajan, Caan BJ, et al: Influence of a Diet Very High in Vegetables, Fruit, and Fiber and Low in Fat on Prognosis Following Treatment for Breast Cancer:
Poljsak B Milisav I, Lampe T et al Strategies for reducing or preventing the generation of oxidative stress. Oxidative Medicine and Cellular Longevity. 2011:9
Powanda MC, Whitehouse MW, Rainsford KD. Celery Seed and Related Extracts with Antiarthritic, Antiulcer, and Antimicrobial Activities. Prog Drug Res. 2015;70:133-53.
Powanda MC and Rainsford KD. A toxicological investigation of a celery seed extract having anti-inflammatory activity. Inflammopharmacology. 2011; 19(4):227-33. Epub 2010 Jun 22.
Qian, S.; Fan, W.; Qian, P.; Zhang, D.; Wei, Y.; Chen, H.; Li, X. Apigenin Restricts FMDV Infection and Inhibits Viral IRES Driven Translational Activity. Viruses 2015, 7, 1613–26.
Rao S, Rehman S, Yu S Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis Clinical and Translational Gastroenterology. 2018 9 (6) p 162.
Radha M. H., Laxmipriya N. P. (2015). Evaluation of biological properties and clinical effectiveness of Aloe vera: a systematic review. J. Tradit. Complement. Med. 5 21–26. 10.1016/j.jtcme.2014.10.006.
Reddy, M.K.; Alexander-Lindo, R.L.; Nair, M.G. Relative inhibition of lipid peroxidation, cyclooxygenase enzymes, and human tumor cell proliferation by natural food colors. J. Agric. Food Chem. 2005, 53, 9268–9273.
Rerksuppaphol S, Rerksuppaphol L. Randomized controlled trial of probiotics to reduce common cold in schoolchildren. Pediatrics International 2012;54(5):682‐7.
Ryu YB, Jeong HJ, Kim JH, et al. Biflavonoids displaying SARS-CoV 3CL (pro) inhibition. Bioorg Med Chem. 2010;18:7940–7.
Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis. 2002;35:1155–1160.
Hempel S, Newberry S, Ruelaz A, et al of probiotics used to reduce risk and prevent or treat disease.Evid Rep Technol Assess (Full Rep). 2011 Apr; (200):1-645
Sanders M, Akkermans L, Haller D et al Safety assessment of probiotics for human use. Gut Microbes. 2010, 1(3): 164–185.
Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007;595:453-70.
Shah BH, et al (1999). Inhibitory effect of curcumin, on platelet-activating factor through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol., 58(7): 1167–72.
Shen CL, Smith BJ, Lo DF et al Dietary polyphenols and mechanisms of osteoarthritis Phytother Res. 2010;24(2):182-5.
Shukla S and Gupta S. Apigenin: A Promising Molecule for Cancer PreventionPharm Res. 2010 Jun; 27(6): 962–978: 10.1007/s11095-010-0089-7
Song J, Park K, Kwon D et al Anti-human rhinovirus 2 activity and mode of action of quercetin-7-glucoside from Lagerstroemia speciosa. J Med Food. 2013 Apr;16(4):274-9. doi: 10.1089/jmf.2012.2290.
Srivastava KC, Bordia A and Verma SK (1995). Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids, 52(4): 223-227.
Sun Z, Yu C, Wang W et al Aloe Polysaccharides Inhibit Influenza A Virus Infection—A Promising Natural Anti-flu Drug Front Microbiol. 2018; 9: 2338. doi: 10.3389/fmicb.2018.02338
Su X, Sangster MY, D’Souza DH (2010) In vitro effects of pomegranate juice and pomegranate polyphenols on foodborne viral surrogates. Foodborne Pathog Dis 7: 1473-1479.
Sundararajan A, Ganapathy R, Huan L, Dunlap JR, Webby RJ, et al. (2010) Influenza virus variation in susceptibility to inactivation by pomegranate polyphenols is determined by envelope glycoproteins. Antiviral Res 88: 1-9.
Syed T. A., Cheema K. M., Ahmad S. A., Holt A. H., Jr. (1996). Aloe vera extract 0.5% in hydrophilic cream versus Aloe vera gel for the management of genital herpes in males. A placebo-controlled, double-blind, comparative study. J. Eur. Acad. Dermatol. Venereol. 7 294–5.
Tang, R.; Chen, K.; Cosentino, M etal. Apigenin-7-O-β-D-Glucopyranoside, an Anti-HIV Principle from Kummerowia Striata. Bioorganic and Medicinal Chemistry Letters 1994, 4, 455–458.
Tannenbaum SR, Wishnok JS, Leaf CD. “Inhibition of nitrosamine formation by ascorbic acid”. The American Journal of Clinical Nutrition. 1991, 53 247–250.
Teixeira V, Valente H, Casal S, et al Antioxidants do not prevent post exercise peroxidation and may delay muscle recovery. Medicine & Science in Sports & Exercise: 2009. 41( 9); 1752-60.
Thomas KJ, Coleman P et al. Use of complementary or alternative medicine in a general population in Great Britain. Results from the National Omnibus Survey. Journal of Public Health 2004; 26:152–57.
Thomas KJ, Nicholl JP, Coleman P. Use and expenditure on complementary medicine in England: a population based survey. Complementary Therapies in Medicine 2001; 9:2–11.
Thomas R, Yang D, Zollaman C. Phytochemicals in Cancer Management. Current Research in Compl and Alt therapy. 2017, 105 (01), pp 2-8.
Thomas R, Butler E, Macchi F and Williams M. Phytochemicals in cancer prevention and management? BJMP 2015, 8 (2), pp 1-9.
Thomas R, Williams M, Sharma H, et al. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014 17(2):180.
Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014 17(2):180.
Tisoncik J, Korth M, Simmons C et al. Into the Eye of the Cytokine Storm Microbiol Mol Biol Rev. 2012 Mar; 76(1): 16–32. doi: 10.1128/MMBR.05015-11
Uchide N, Toyoda H Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules. 2011. 28; 16(3):2032-52.
Wang X, Ouyang Y, Liu J et al, Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014 Jul 29; 349; 4490.
Welliver R, Monto AS, Carewicz O et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA. 2001; 285: 748-754
WHO report – Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. 2001. . http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf
World Health Organization. [Last accessed on 2020, 1.4.2020]. Available from: http://www.who.int .
World Gastroenterology Organisation. Probiotics and prebiotics . 2017.
Wu W, Li R, Xianglian Li X, et al Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses. 2016 Jan; 8(1): 6.
Yang ZF, Bai LP, Huang WB et al. Comparison of in vitro antiviral activity of tea polyphenols against influenza A and B viruses and structure-activity relationship analysis. Fitoterapia. 2014; 93:47-53
Yagi A, Byung P (2015). Immune modulation of Aloe vera: acemannan and gut microbiota modulator. J. Gastroenterol. Hepatol. Res. 4 1707–1721. 10.17554/j.issn.2224-3992.2015.04.525.
Yao X, Ye F, Zhang M et al.In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020; (published online March 2020) DOI:10.1093/cid/ciaa237
Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, et al. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett. 2012;22:4049–54.
Zhou Y, Fu B, Zheng X et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients PERSPECTIVE IMMUNOLOGY https://academic.oup.com/nsr/advance-article-pdf/doi/10.1093/nsr/nwaa041/32901656/nwaa041.pdf
Zhou Y, Fu B, Zheng X et al Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients (2020). National Science Review, nwaa041, https://doi.org/10.1093/nsr/nwaa041