Defending Yourself
Against Virus Infections

Editor’s note: As we go to press, reports indicate that the swine flu is spreading far more widely than official data represents, with outbreaks in Europe and Asia now showing that it is gaining a foothold in two additional regions.1 In the U.S., according to the Centers for Disease Control (CDC), only 1 of 20 cases have been reported, with total infected now exceeding 100,000 people. This ratio of reported/unreported cases is thought to be extremely greater in the U.K. where it is estimated to be 1/300. According to the World Health Organization’s (WHO’s) prior definition, the spread of a virus in at least two regional areas meets the criteria of a pandemic. Yet the whistle has not yet been blown!

In another article,2 politically-minded health officials have expressed concern that shouting “pandemic” could lead to confusion and loss of confidence in public announcements. U.K. Health Secretary Alan Johnson believes that WHO should be more flexible in its determination about whether the new virus is serious enough to raise the pandemic alert to the highest level.

While the illnesses caused by the swine flu have been mild to date, “It is very possible that this virus will continue to circulate and cause illness again next winter,” said CDC’s Anne Schuchat. Furthermore, whether it will be more virulent or less so “is not predictable right now.”

  1. Gale J. Swine flu is spreading wider than official data show. Bloomberg, May 25, 2009.
  2. Doherty D, Gale J. WHO may alter pandemic alert system after U.K. cites confusion. Bloomberg, May 27, 2009.

By Durk Pearson & Sandy Shaw ©2009

erious threats to human populations from newly developed, and indeed old but still dangerous, infectious viruses continue to appear unpredictably and can kill large numbers of people. In the United States alone, ordinary influenza kills about 36,000 people a year.

Government public health authorities (CDC, FEMA, FDA, Homeland Security, etc.) are attempting to prevent and control viral outbreaks and approve antiviral therapies, but you should recognize that while these government agencies employ scientists, they are led by political appointees. Furthermore, public health agencies are focused on protecting the health of the herd, not the individual.

We decided to evaluate the peer-reviewed scientific literature indexed by the National Library of Medicine on natural products for those that have useful antiviral effects at safe dosages.

The evidence led us to a protective combination that consists of the flavonoid quercetin, green tea extract, resveratrol, N-acetylcysteine, vitamin D, and vitamin C. These ingredients have been reported to have significant anti-viral effects in cell culture and animal studies, and in a few human clinical trials.

Quercetin

Influenza viruses depend on an enzyme that their RNA codes for called neuraminidase. The two prescription drugs that are useful against the current H1N1 swine/avian flu are neuraminidase inhibitors, Tamiflu® and Relenza®. Much to our delight there are natural food constituents such as quercetin that are neuraminidase inhibitors.

The flavonoid quercetin is found widely in vegetables and fruits and is especially high amounts in apples, cranberries, blueberries, and onions, as well as black tea, red wine, and various fruit juices.10 An extensive critical review of its safety10 concluded: “The dose levels in the long-term animal studies at which no toxicologically significant adverse effects were reported support the addition of food-grade quercetin to foods at levels resulting in exposure estimates approximating intakes of naturally-occurring quercetin from the diet by consumers with a high fruit and vegetable intake (i.e. 200–500 mg/day). In fact, in Japan, quercetin is approved as a food additive under the “List of Existing Food Additives” (Ministry of Health, Labour, and Welfare, Japan, 1996).

Quercetin supplements were used to evaluate the flavonoid’s effects on the incidence of upper respiratory tract infections (URTI) in trained male cyclists after intensive exercise.11 Forty subjects were randomized to receive either 1000 mg/day quercetin or placebo before, during and for 2 weeks after a 3 day period during which they cycled for 3 hours/day at approximately 57% Wmax. While quercetin (as compared to placebo) did not alter exercise-induced changes in several measures of immune activity, it “significantly reduced URTI (upper respiratory tract infection) in cyclists during the 2-wk period after intensified exercise.” The results were based upon self-report of symptoms rather than a medical diagnosis.

In another study,12 quercetin reduced the susceptibility to infection of mice exposed to H1N1 influenza virus following 3 days of stressful exercise. As the authors note: “The effects associated with exercise stress are not unlike those that have resulted in other stress paradigms, such as psychological stress, which has been shown to alter infectivity of a variety of pathogens, including HIV-1 and influenza.” The treated mice were given 12.5 mg/kg quercetin by oral gavage daily in 200 µl of Tang. The exercised mice that did not receive quercetin experienced a 91% incidence of infection, while the incidence of infection was 67% in the exercised-quercetin group. Mortality was 74% in the exercised placebo mice, but was only 52% in the exercised-quercetin group. While there was no difference between the exercised-quercetin group and the not-exercised/placebo group, there was a trend toward a beneficial effect of quercetin in the not-exercised/quercetin group.

Other papers13,14 have reported in vitro studies showing anti-viral effects of quercetin on herpes simplex virus-1 and adenovirus-3, polio virus type 1, parainfluenza virus type 3 and respiratory syncytial virus (RSV).

Interestingly, another paper15 has reported that there is an essential requirement for reduced glutathione (GSH) for the anti-oxidant effect of quercetin. As mentioned below, N-acetylcysteine increases the supplies of intracellular cysteine needed to maintain high levels of reduced glutathione. Hence, inclusion of NAC in combination with quercetin should help prevent any possible pro-oxidant effects of quercetin. Moreover, another paper16 reported that quercetin (as well as onion extract, which is rich in quercetin) increased intracellular glutathione concentration in cell culture by about 50%. The mechanism for the latter effect was an increased expression of gamma-glutamylcysteine synthetase, the rate limiting enzyme in the synthesis of reduced glutathione.

Resveratrol

A recent paper1 reported beneficial effects against the influenza A virus in both cell culture and in influenza-virus infected mice. The resveratrol treated influenza-infected mice had significantly improved survival and decreased pulmonary viral titers (98% lower) as compared to the non-treated influenza-infected mice. The data indicated that resveratrol’s antiviral activity in cell culture was “largely related to its inhibition of virus life-cycle steps that occur 1–9 hours after infection . . .” No significant inhibition of viral replication occurred when resveratrol was added to culture 9 hours after infection. The authors’ study of possible mechanisms of resveratrol’s antiviral effects in cell culture led them to conclude that “[o]ur data strongly suggest that RV’s [resveratrol’s] antiviral effects are related to the inhibition of PKC [protein kinase C, an intracellular signaling molecule] activity and its dependent pathways.” In other words, resveratrol interfered with infection by altering cellular pathways, rather than acting directly against the virus itself.

The mice were inoculated with virus and, one hour later, given i.v. resveratrol at a dosage of 1 mg/kg/day or placebo, with treatments repeated daily for the next 7 days. Only 20% of the infected mice treated with placebo were alive by 10 days after infection, whereas 40% of the resveratrol-treated infected mice survived to day 10. As the authors explained, “[n]one of the mice that survived to day 10 after infection showed any signs of disease for the next 3 months and were considered to be cured.”

Vitamin D

Whoever wishes to investigate medicine properly should proceed thus: in the first place to consider the seasons of the year . . .
— Hippocrates (circa 400 BC)

There is a very interesting story concerning the discovery by R. Edgar Hope-Simpson, a general practitioner, that exposure to a “seasonal stimulus” associated with solar radiation explained the remarkable seasonality of epidemic influenza.2 For the entire story, see reference 2. Hope-Simpson’s “seasonal stimulus” turned out to be vitamin D.

Human volunteers “inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter.” Also, vitamin D deficiency has been shown to be a predisposing factor for children to become infected by influenza. Serum levels of vitamin D are low in many people of all ages, but especially in the elderly (who can make only about 25% of the vitamin D made by the young exposed to the same amount of sunlight) during the winter. Moreover, in badly polluted cities (such as Mexico City), high levels of ozone in the atmosphere filter out the UVB that enables people to manufacture vitamin D in their skin. In fact, one report cited in reference 2 explained that “no vitamin D is made in the skin at latitude 52N (the latitude of London) from about October to March because atmospheric ozone easily filters out UVB radiation unless the sun is high enough in the sky.”

It has been reported that three independent research groups2 have shown that 1,25(OH)2D, the biologically active form of vitamin D, “dramatically” stimulates genetic expression of antimicrobial peptides (AMP) by human monocytes, neutrophils, and other immune cells. These AMPs include defensins and cathelicidins that have broad spectrum antimicrobial activity, including antiviral activity. They have been reported to inactivate the influenza virus.3

At the same time that vitamin D stimulates expression of genes that create antimicrobial peptides, it is also reported to “dampen certain arms of the adaptive immune system, especially those responsible for the signs and symptoms of acute inflammation, such as the cytokine storms operative when influenza kills quickly.”4 Hence, vitamin D acts as both an immune stimulant and an anti-inflammatory. In relation to seasonality and vitamin D’s suppression of killer cytokine storms, the first wave of the 1918 influenza (A/M1N1) pandemic in the spring was mild, whereas 6 months later in fall and winter, there was a second wave with much higher mortality.

The greatest mortality during the 1918 pandemic was among previously healthy young adults, not the very young or very old as is the case with the ordinary flu. The actual cause of death in many cases is thought to have been a suicidally effective storm of inflammatory cytokines which were not as potent in the elderly and the young. The current H1N1 swine/avian flu epidemic in Mexico appears to be exhibiting the same age-related pattern of mortality as the 1918 pandemic. While the modern widespread use of sun screens does help to protect the skin from the ravages of UV, sunscreens block vitamin D synthesis. The safest source of vitamin D is a capsule.

Important Notes

Your first line of defense against the flu is hand washing. Most flu infections occur via hand-to-mouth, hand-to-nose, and hand-to eye transmission. Most aerosol particles produced by coughing and sneezing quickly settle out onto objects in the environment. People touch their faces hundreds of times per day, usually without noting it or realizing it. We think that the biggest effect of wearing a gauze mask is to help interrupt the hand to mouth/nose infection route, though N-95 respirators can filter out small long-lasting aerosol particles. We suggest carrying a small flip top squeeze bottle of rubbing alcohol with you, for convenient anywhere/anytime hand washing. (Remember that rubbing alcohol is flammable, so don’t use it near flames or while smoking.)

This formula is NOT intended as a replacement for the prescription drugs Tamiflu and Relenza. If you develop the symptoms of a flu infection, see your doctor immediately to get a prescription, and start taking the drug promptly at the prescribed dose. To be effective, these drugs must be taken within 48 hours after developing flu symptoms, and it may be difficult to obtain an appointment with your physician this rapidly, particularly if there are a large number of other people developing flu symptoms at the same time in your area.

Most people exposed to the flu, even during the 1918 pandemic, did not become symptomatic. Flu infections are often so mild that no symptoms develop. This formula is designed to support your immune system’s natural defensive functions. It is not a magic bullet. Take it when flu infections are in your neighborhood, but do not delay seeing a doctor if you develop symptoms. If you become symptomatic, you can take this in addition to Tamiflu or Relenza, but do NOT use this formula as a substitute for these prescription drugs.

Antiviral Effect of Green Tea Catechins

A recent paper5 reports on the antiviral effect of catechins in green tea on three different subtypes of influenza virus (including A/H1N1, the avian flu) in cell culture (MDCK, Madin-Darby canine kidney cells). EGCG (epigallocatechin gallate) was the most effective, completely inhibiting viral replication (detected by the release of new virus) at 120 µM. EGCG (and to a lesser extent EGC (epigallocatechin) were effective, though at high concentrations (350 µM for EGCG and 550 µM for EGC), in inhibiting neuraminidase, an enzyme thought to play a key role in the release of newly made virus particles.5 In fact, the drugs Tamiflu® and Relenza® act by inhibiting neuraminidase.

The authors note that EGCG has been reported to be a “strong inhibitor” of HIV replication in cultured peripheral blood cells and to have antiviral activity against Epstein-Barr virus, as well as citing previous studies in which it has shown inhibition of influenza virus in cell cultures.

Work is also being done on semi-synthetic catechin derivatives, altering catechin molecular structure in an attempt to discover even stronger antivirals.6 Although we suspected that this particular study was funded by a pharmaceutical company, it was actually funded in part by the Chemical & Biological Terrorism Research Fund from the Ministry of Commerce, Industry and Energy and Nanobiotechnology Research Initiatives (which may represent government support of pharmaceutical companies) from the Ministry of Science and Technology of the South Korean government.

If you drink green tea, you might be interested in the results of another study7 which reported that gargling with tea catechin extract solution significantly reduced the incidence of influenza infection (1.3% of those gargling the catechin solution became infected as compared to 10% of those gargling a placebo non-catechin solution). The tea catechin extract solution was gargled by 76 residents of a nursing home in Japan, mean age 83 ±8.2 years, compared with 48 age and sex matched residents who gargled without tea catechin extract solution. All residents were given influenza vaccinations until early December 2004, followed by the gargling experiments during January to March 2005.

N-Acetylcysteine

N-acetylcysteine acts as a delivery vehicle for getting cysteine efficiently into cells. (Cysteine itself is also imported into cells, but not as effectively as N-acetylcysteine.) Once cysteine is inside the cell, it is used (among other things) to manufacture the major cellular antioxidant glutathione, which is important in immune protection against viral infection.8 In fact, glutathione has been reported to inhibit influenza infection in cultured cells and in mice.8A Virus infections cause a shift to a pro-oxidant state in the cells and body fluids of patients infected with HIV or hepatitis C, as well as in the lungs of mice infected with influenza,8 with rapid decreases in glutathione levels in viral infections with an acute onset (lesser decreases also accompany chronic viral infections). Hence, maintaining high glutathione levels is a first line defense against viruses.

A six month study of N-acetylcysteine (NAC) treatment (versus placebo) in human patients with non-respiratory chronic degenerative diseases evaluated NAC effects on influenza and influenza-like episodes.9 (Episodes occurred as a result of natural infection, rather than as a result of an administered attenuated virus.) A total of 262 subjects of both sexes were randomized to receive either placebo or NAC tablets (600 mg twice daily for six months). The authors found that “[b]oth local and systemic symptoms were sharply and significantly reduced in the NAC group.” They further found that “[f]requency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. As the authors explain, the dose chosen was based on the “extensive clinical experience showing the high tolerability” of N-acetylcysteine.

The authors concluded: “N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease.”

Vitamin C

Studies of animal models have reported finding protective effects of vitamin C against the negative consequences of glutathione deficiency.17, 18 For example, glutathione deficiency in newborn rats and guinea pigs, animals that cannot make ascorbic acid (though adult rats can), is lethal but death was prevented by administration of high doses of ascorbic acid.17 (Glutathione also protects against vitamin C deficiency; scurvy induced by vitamin C deficiency in guinea pigs was significantly delayed by administration of glutathione monoethyl ester.17)

Moreover, vitamin C is an antiinflammatory molecule19 and has been reported to protect against excessive immune stimulation of inducible nitric oxide (as occurs in sepsis) synthesis.20

There is another reason for the large amount of vitamin C. Both N-acetylcysteine and its metabolite cysteine are extremely soluble in urine. Their oxidation product, cystine, has a very low solubility in urine, and has the potential to form cystine stones in the kidneys and urinary bladder. We have found that by using twice the amount of vitamin C as cysteine or N-acetylcysteine, this oxidation to cystine can be prevented. If you collect your urine after taking supplemental gram+ doses of N-acetylcysteine or cysteine itself, and leave it exposed to the air, a white precipitate of cystine will form as the cysteine oxidizes. This process can be delayed by taking additional vitamin C. Note, too, that influenza infections promote an increasingly oxidative state in your body.

References

1. Palamara et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis 191:1719–29 (2005).
2. Cannell et al. Epidemic influenza and vitamin D. Epidemol Infect134:1129–40 (2006).
3. Daher et al. Direct inactivation of viruses by human granulocyte defensins. J Virol 60:1068–74 (1986).
4. Cannell et al. On the epidemiology of influenza. Virol J 5:29 (2008) doi:10.1186/1743–422X-5-29.
5. Song et al. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 68:66–74 (2005).
6. Song et al. Biological evaluation of anti-influenza viral activity of semi-synthetic catechin derivatives. Antiviral Res 76:178–85 (2007).
7. Yamada et al. Gargling with tea catechin extracts for the prevention of influenza infection in elderly nursing home residents: a prospective clinical study. J Altern Complement Med 12(7):669–72 (2006).
8. Nencioni et al. Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. FASEB J. 10.1096/fj.02-0508-fje (Published online Feb. 19, 2003).
8A. Cai et al. Inhibition of influenza infection by glutathione. Free Radic Biol Med 34(7):928–36 (2003).
9. De Flora et al. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 10:1535–41 (1997).
10. Harwood et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45:2179–205 (2007).
11. Nieman et al. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc 39(9):1561–9 (2007).
12. Davis et al. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol 295:R505–9 (2008).
13. Kaul et al. Antiviral effect of flavonoids on human viruses. J Med Virol 15:71–9 (1985).
14. Chiang et al. In vitro antiviral activities of Caesalpinia pulcherrima and its related flavonoids. J Antimicrob Chemother 52:194–8 (2003).
15. Ferraresi et al. Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin. Free Radic Res 39(11):1249–58 (2005).
16. Myhrstad et al. Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Free Radic Biol Med 32(5):386-93 (2002).
17. Briviba and Sies. Nonenzymatic antioxidant defense systems in natural antioxidants in Human Health and Disease, pg. 111, edited by Balz Frei (Academic Press, 1994).
18. Anderson. Glutathione and glutathione delivery compounds, pp. 68-9, in Antioxidants in Disease Mechanisms and Therapy, edited by Helmut Sies (Academic Press, 1997).
19. Wannamethee et al. Association of vitamin C status, fruit and vegetable intakes, and markers of inflammation and hemostasis, Am J Clin Nutr 83:567–74 (2006).
20. Wu et al. Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression. Free Radic Biol Med 37(8):1282–9 (2004).


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