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Rauthschild’s EVA-10 Complex

Research and Development

Our research and development focus is on viral and neoplastic disease. Our basic research and drug discovery is carried out at Rauthschild’s Pharmaceutical, Inc., in Oceanside,

California. The early work on the fractions of EVA-10 was conducted at research institutes and universities around the world. In recent years, SARS and avian influenza (H5N1) have emerged in Asia to wreck havoc on public health and economic sectors. Since Southern China is postulated as the epicenter of emerging viruses due to its

agricultural-based communities and high population density, Rauthschild’s has positioned itself on the front line of this by synthesizing the collective body of scientific and medical research literature to create the most advance botanical anti- viral and anti-cancer product research in the world. Based on the most current clinical findings

from our worldwide network, Rauthschild’s Research Group is responsible for the development of a broad spectrum platform technology that has proven to have downstream applications for SARS, Influenza, Herpes, HIV, Bird Flu (H5N1) and

cancer. Results from multi-center study showed our platform to be effective in inactivating SARS CoV, Staphylococcus aureus, Steptococcus pneumonia, human influenza (H3N2), and bird flu (H5N1) and is the source material for the development of our ethical pharmaceutical drug candidates.

The traditional pharmaceutical paradigm does not work for emerging viral disease

We are living in an age where the phrase "emerging virus" has taken its place in our general vernacular. Emerging viruses such as SARS CoV, and H5N1 have taken world stage in terms of posing significant threats to humanity. Why then, are we not able to

effectively combat these viruses? The answer is buried in the very essence of the existing pharmaceutical/FDA paradigm. This paradigm works well for most diseases. For a new drug to enter the market, it must go through a lengthy approval process. In general, this process takes from 5 to 10 years. While this paradigm produces effective

drugs for diseases such as arthritis and diabetes, it does not work for diseases caused by emerging viruses. Under the existing pharmaceutical/FDA paradigm, once a new virus emerges, there are essentially two options. The first option is to use outdated

anti-viral drugs (outdated in the sense that they were developed years earlier for different viruses) and just hope that something works. The second option is to spend the next 5 to 10 years developing a new drug that will ultimately be too late to save countless lives. Neither option works for emerging viruses. The SARS outbreak is a

perfect example. The standard treatment protocol was to use ribavarin and steroid combination therapy. This was not only ineffective but ultimately caused severe and permanent damage to many patients "lucky" enough to survive the illness. We are now facing a similar but much larger problem with Bird Flu. A second problem with the

traditional pharmaceutical approach, concerns the use of synthetic molecules designed to target one aspect of disease. Again, this approach may be useful for "garden variety" disease but fails when it comes to viral disease. Viruses are not static and

they are constantly mutating and changing the "therapeutic targets". This leads to drug resistance and the drug quickly become ineffective.

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The comprehensive approach

Our approach has been to combine non-toxic, anti-viral compounds, each directed at a

specific component of the relevant viruses life cycle. A pharmaceutical drug version of this “cocktail” approach has been used against viruses such as HIV with reasonably good success. However, the inherent toxicities associated with these drugs continue

to be a major limiting factor for their practical use. To overcome this limitation, Rauthschild utilize anti-viral fractions isolated from botanical sources with well-established safety profiles. Botanicals are excellent source materials as numerous plants contain highly effective anti-microbial defense molecules that are entirely safe

for human consumption. These anti-viral formulations are delivered as an oral liquid allowing fractional dosing, ease of administration, and rapid GI mucosal, GI luminal targets and systemic delivery of anti-viral components. EVA-10 is Rauthschild’s proprietary broad spectrum anti-microbial anti-viral platform technology. Components of EVA-10 have been characterized in multi-center, anti- viral projects. Broad in its effectiveness against microbes suggesting its ant-viral target is a

very ancient and highly conserved feature of microbes. Therefore, it follows that it is unlikely that viruses and bacteria will be able to develop resistance against EVA-10. EVA10 – RAUTHSCHILD NEW DRUG EVA-10 COMPLEX CANDIDATES FOR THE TREATMENT OF AVIAN INFLUENZA, HERPES, HIV, SARS AND CERTAIN NEOPLASIA

EVA-10 is composed of four theaflavin isomers (EVA-10a-c). These are only are some of the major components of the complex Rauthschild utilizes for the treatment and prevention of AVIAN INFLUENZA and other viral disease. This mixture of these molecules (EVA-10a-c) is extremely effective at inhibiting the

replication of SARS CoV in Vera cells. Recently, EVA-10b'' and EVA-10c we both shown to strongly inhibit the SARS-CoV 3C-like Protease Activity (Chen et al., Evid Based Complement Alternat Med. 2005 Jun;2(2):209-215). The IC (50) was 7 microM and 9.5 microM respectively. The virally encoded 3C-like protease (3CLPro) is critical for the viral replication of SARS-CoV in infected host cells and is one of the most promising targets for anti-

SARS-CoV drugs EVA-10a, EVA-10b'b'' and EVA-10C each inhibits the infectivity of H5N1 virus in MDCK

cells. EVA-10c works by blocking the uptake of the virus into cells (EC50 2.9 uG./ml).

EVA-10 Facts for Treatment of Viral Infections: Reduces duration of influenza illness. Inhibits H5N1 infections in chick embryos.

Inhibit H5N1 infections in cells. Blocks the uptake of H5N1 in cells. Blocks viral replication.

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Emerging Viruses

After a century of prevention and control efforts, infectious disease remains the most problematic public health and global destabilizing issue facing mankind. Insidious by nature, infectious disease directly causes 13 million deaths and contributes to the death of many millions annually. These numbers are increasing as a direct result of global economic, technology, environmental degradation and environment microorganism interaction. Synergistic interplay of these parameters drive the emergence of new diseases, the re-emergence of diseases once controlled, and the development of antimicrobial resistance Our biologic world is not static. The concept of “emerging infectious diseases”

appeared in the late 1980s, when major disease outbreaks occurred around the globe and surprised many scientists who considered infectious diseases to be maladies of the past or limited to the under-developed regions of the world. Viruses, especially RNA viruses, with their ability to adapt quickly to changing environmental conditions, are

among the most prominent causes of emerging infectious diseases. Nearly all of these emergent disease episodes have involved zoonotic or species- jumping infectious agents. New viral zoonotic diseases, such as acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency viruses 1 or 2, emerged in the 1980s and

1990s, and have become established in the human population. Influenza virus continues to find new ways to move from avian species into humans. The filoviruses and the newer paramyxo viruses, Hendra and Nipah, highlight the increasing proclivity

of some animal viral agents to infect human populations with devastating results. A previously unknown transmissible spongiform encephalopathy, bovine spongiform encephalopathy, has emerged in cattle in Europe and spread to humans as well as other animal species. Emerging viruses usually have identifiable sources, often existing

viruses of animals or humans that have been given opportunities to infect new host populations ("viral traffic"). The reservoirs are often infected subclinically or asymptomatically and the distribution of the diseases reflects the range and the

population dynamics of their reservoir hosts. In addition, bioterrorism has become an important factor which must now also be considered in infectious disease emergence/re-emergence.

Extensive outbreaks of zoonotic disease are not uncommon, especially as the disease is often not recognized as zoonotic at the outset and may spread undetected for some time.

Environmental and social changes, frequently the result of human activities, can accelerate viral traffic, with consequent increases in disease emergence. The complex interaction of factors, such as environmental and ecological changes, social factors, decline of health care, human demographics and behavior, influences the emergence or re-emergence of such diseases. Increasing numbers of emerging viral disease episodes seem to be linked to a decline in global resources for proven public health programs, agricultural extension programs, and the like, programs that have stood in the way of the spread and evolution of viral pathogens. These factors, combined with the ongoing evolution of viral and microbial variants, make it likely that emerging infections will continue to appear and probably increase.

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Influenza

Epidemics of influenza typically occur during the winter months in temperate regions and have been responsible for an average of approximately 36,000 deaths/year in the United States during 1990–1999. Influenza viruses also can cause pandemics, during which rates of illness and death from influenza-related complications can increase

worldwide. Influenza viruses cause disease among all age groups. Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged > 65 years, children aged <2 years, and persons of any age who have

medical conditions that place them at increased risk for complications from influenza. Influenza vaccination is the primary method for preventing influenza and its severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination are 1) persons at increased risk for influenza-related complications (i.e., those aged > 65 years, children aged 6–23 months, pregnant women, and persons of any age with certain chronic medical conditions); 2) persons aged 50--64 years because this group has an elevated prevalence of certain chronic medical conditions; and 3) persons who live with or care for persons at high risk (e.g., health-care workers and household contacts who have frequent contact with persons at high risk and who can transmit influenza to those persons at high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed, chiefly among persons aged <65 years who are at increased risk for influenza-related complications among all racial and ethnic groups, among blacks and Hispanics aged > 65 years, among children aged 6–23 months, and among health-care workers. ACIP recommends using strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs. Although influenza vaccination remains the cornerstone for the control and treatment of influenza, information on antiviral medications is also presented because these agents are an adjunct to vaccine. Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Influenza B viruses are not

categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. In 2001, influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses began circulating widely. Both influenza A and B viruses

are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.

Immunity to the surface antigens, particularly the hemagglutinin, reduces the

likelihood of infection and severity of disease if infection occurs. Antibody against one

influenza virus type or subtype confers limited or no protection against another type or

subtype of influenza. Furthermore, antibody to one antigenic variant of influenza virus might not completely protect against a new antigenic variant of the same type or

subtype. Frequent development of antigenic variants through antigenic drift is the

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virologic basis for seasonal epidemics and the reason for the usual incorporation of one

or more new strains in each year's influenza vaccine.

Clinical signs and symptoms of influenza. Influenza viruses are spread from person to person primarily through the coughing and sneezing of infected persons. The typical incubation period for influenza is 1–4 days, with an average of 2 days. Adults can be infectious from the day before symptoms begin through approximately 5 days after illness onset. Children can be infectious for > 10 days, and young children can shed virus for several days before their illness onset. Severely immune compromised persons can shed virus for weeks or months. Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness. Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone. Reported sensitivities and specificities of clinical definitions for influenza-like illness (ILI) in studies primarily among adults that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture. Sensitivity and predictive value of clinical definitions can vary, depending on the degree of co-circulation of other respiratory pathogens and the level of influenza activity. A study among older nonhospitalized patients determined that symptoms of fever, cough, and acute onset had a positive predictive value of 30% for influenza, whereas a study of hospitalized older patients with chronic cardiopulmonary disease determined that a combination of fever, cough, and illness of <7 days was 78% sensitive and 73% specific for influenza). However, a study among vaccinated older persons with chronic lung disease reported that cough was not predictive of influenza infection, although having a fever or feverishness was 68% sensitive and 54% specific for influenza infection. Influenza illness typically resolves after 3–7 days for the majority of persons, although cough and malaise can persist for >2 weeks. Among certain persons, influenza can

exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a coinfection with other viral or bacterial pathogens. Young children with influenza infection can have initial symptoms mimicking bacterial sepsis with high fevers, and <

20% of children hospitalized with influenza can have febrile seizures. Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis.

Hospitalizations and deaths from influenza.

The risks for complications, hospitalizations, and deaths from influenza are higher

among persons aged > 65 years, young children, and persons of any age with certain

underlying health conditions (see Persons at Increased Risk for Complications) than among healthy older children and younger adults). Estimated rates of influenza-

associated hospitalizations have varied substantially by age group in studies conducted

during different influenza epidemics.

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Among children aged 0–4 years, hospitalization rates have ranged from approximately 500/100,000 children for those with high-risk medical conditions to 100/100,000

children for those without high-risk medical conditions. Within the 0–4 year age group, hospitalization rates are highest among children aged 0–1 years and are comparable to rates reported among persons aged > 65 years. During influenza epidemics from 1979–80 through 2000–01, the estimated overall

number of influenza-associated hospitalizations in the United States ranged from approximately 54,000 to 430,000/epidemic. An average of approximately 226,000 influenza-related excess hospitalizations occurred per year, with 63% of all

hospitalizations occurring among persons aged > 65 years. Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A (H3N2) viruses. Influenza-related deaths can result from pneumonia and from exacerbations of cardiopulmonary

conditions and other chronic diseases. Deaths of older adults account for > 90% of deaths attributed to pneumonia and influenza. In one study of influenza epidemics, approximately 19,000 influenza-associated pulmonary and circulatory deaths per

influenza season occurred during 1976–1990, compared with approximately 36,000 deaths during 1990--1999. Estimated rates of influenza- associated pulmonary and circulatory deaths/100,000 persons were 0.4--0.6 among persons aged 0–49 years, 7.5 among persons aged 50--64 years, and 98.3 among persons aged > 65 years. In

the United States, the number of influenza-associated deaths might be increasing in part because the number of older persons is increasing. In addition, influenza seasons in which influenza A (H3N2) viruses predominate are associated with higher mortality; influenza A (H3N2) viruses predominated in 90% of influenza seasons during 1990–

1999, compared with 57% of seasons during 1976–1990. Deaths from influenza are uncommon among both children with and without high- risk conditions, but do occur). A study that modeled influenza-related deaths estimated

that an average of 92 deaths (0.4 deaths per 100,000) occurred among children aged <5 years annually during the 1990's, compared with 32,651 deaths (98.3 per 100,000) among adults aged > 65 years. Reports of 153 laboratory- confirmed influenza-related pediatric deaths from 40 states during the 2003–04 influenza season

indicated that 61 (40%) were aged <2 years and, of 92 children aged 2–17 years, 64 (70%) did not have an underlying medical condition traditionally considered to place a person at risk for influenza-related complications (CDC, National Center for Infectious

Diseases, unpublished data, 2005). Further information is needed regarding the risk for severe influenza-complications and optimal strategies for minimizing severe disease and death among children.

Avian Influenza (H5N1)Avian influenza in birds.

Avian influenza is an infection caused by avian (bird) influenza (flu) viruses. These influenza viruses occur naturally among birds. Wild birds worldwide carry the viruses in their intestines, but usually do not get sick from them. However, avian influenza is

very contagious among birds and can make some domesticated birds, including chickens, ducks, and turkeys, very sick and kill them. Infected birds shed influenza virus in their saliva, nasal secretions, and feces. Susceptible birds become infected

when they have contact with contaminated secretions or excretions or with surfaces that are contaminated with secretions or excretions from infected birds. Domesticated birds may become infected with avian influenza virus through direct contact with infected waterfowl or other infected poultry, or through contact with surfaces (such as

dirt or cages) or materials (such as water or feed) that have been contaminated with

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the virus. Infection with avian influenza viruses in domestic poultry causes two main forms of disease that are distinguished by low and high extremes of virulence. The “low pathogenic” form may go undetected and usually causes only mild symptoms (such as

ruffled feathers and a drop in egg production). However, the highly pathogenic form spreads more rapidly through flocks of poultry. This form may cause disease that affects multiple internal organs and has a mortality rate that can reach 90- 100% often within 48 hours.

Human infection with avian influenza. There are many different subtypes of type A influenza viruses. These subtypes differ because of changes in certain proteins on the surface of the influenza A virus (hemagglutinin [HA] and neuraminidase [NA] proteins). There are 16 known HA

subtypes and 9 known NA subtypes of influenza A viruses. Many different combinations of HA and NA proteins are possible. Each combination represents a different subtype. All known subtypes of influenza A viruses can be found in birds. Usually, “avian influenza virus” refers to influenza A viruses found chiefly in birds, but infections with

these viruses can occur in humans. The risk from avian influenza is generally low to most people, because the viruses do not usually infect humans. However, confirmed cases of human infection from several subtypes of avian influenza infection have been reported since 1997. Most cases of avian influenza infection in humans have resulted

from contact with infected poultry (e.g., domesticated chicken, ducks, and turkeys) or surfaces contaminated with secretion/excretions from infected birds. The spread of avian influenza viruses from one ill person to another has been reported very rarely,

and transmission has not been observed to continue beyond one person. “Human influenza virus” usually refers to those subtypes that spread widely among humans. There are only three known A subtypes of influenza viruses (H1N1, H1N2 and H3N2) currently circulating among humans. It is likely that some genetic parts of current human influenza A viruses came from birds originally. Influenza A viruses are constantly changing, and they might adapt over time to infect and spread among humans. During an outbreak of avian influenza among poultry, there is a possible risk to people who have contact with infected birds or surfaces that have been contaminated with secretions or excretions from infected birds. Symptoms of avian influenza in humans have ranged from typical human influenza- like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases (such as acute respiratory distress), and other severe and life-threatening complications. The symptoms of avian influenza may depend on which virus caused the infection.

Avian influenza A (H5N1).

Influenza A (H5N1) virus – also called “H5N1 virus” – is an influenza A virus subtype that occurs mainly in birds, is highly contagious among birds, and can be deadly to them. Outbreaks of avian influenza H5N1 occurred among poultry in eight countries in Asia (Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand, and Vietnam)

during late 2003 and early 2004. At that time, more than 100 million birds in the affected countries either died from the disease or were killed in order to try to control

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the outbreaks. By March 2004, the outbreak was reported to be under control. Since late June 2004, however, new outbreaks of influenza H5N1 among poultry were

reported by several countries in Asia (Cambodia, China [Tibet], Indonesia, Kazakhstan, Malaysia, Mongolia, Russia [Siberia], Thailand, and Vietnam). It is believed that these outbreaks are ongoing. Influenza H5N1 infection also has been reported among poultry in Turkey Romania, and Ukraine. Outbreaks of influenza H5N1 have been reported

among wild migratory birds in China, Croatia, Mongolia, and Romania. Human cases of influenza A (H5N1) infection have been reported in Cambodia, China, Indonesia, Thailand, and Vietnam.

Human health risks during the H5N1 outbreak.

H5N1 virus does not usually infect people, but more than 140 human cases have been

reported by the World Health Organization since January 2004. Most of these cases have occurred as a result of people having direct or close contact with infected poultry or contaminated surfaces; however, a few cases of human-to-human spread of H5N1

have occurred. Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of detected cases of severe disease and death in humans. In the current outbreaks in Asia and Europe, more than half of those infected with the virus have died. Most cases have occurred in previously healthy children and young adults. However, it is possible that the only cases currently being reported are those in the most severely ill people, and that the full range of illness caused by the H5N1 virus has not yet been defined. So far, the spread of H5N1 virus from person to person has been rare and has not continued beyond one person. Nonetheless, because all influenza viruses have the ability to change, scientists are concerned that H5N1 virus one day could be able to infect humans and spread easily from one person to another. Because these viruses do not commonly infect humans, there is little or no immune protection against them in the human population. If H5N1 virus were to gain the capacity to spread easily from person to person, an influenza pandemic (worldwide outbreak of disease) could begin. An influenza pandemic is a global outbreak of disease that occurs when a new influenza A virus appears or “emerges” in the human population, causes serious

illness, and then spreads easily from person to person worldwide. Pandemics are different from seasonal outbreaks or “epidemics” of influenza. Seasonal outbreaks are caused by subtypes of influenza viruses that already circulate among people, whereas pandemic outbreaks are caused by new subtypes, by subtypes that have never

circulated among people, or by subtypes that have not circulated among people for a long time. Past influenza pandemics have led to high levels of illness, death, social disruption, and economic loss.

Emergence of Pandemic Influenza viruses.

There are many different subtypes of Influenza or “flu” viruses. The subtypes differ based upon certain proteins on the surface of the virus (the hemagglutinin or “HA”

protein and the neuraminidase or the “NA” protein). Pandemic viruses emerge as a result of a process called "antigenic shift,” which causes an abrupt or sudden, major change in influenza A viruses. These changes are caused by new combinations of the HA and/or NA proteins on the surface of the virus. Such

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changes result in a new influenza A virus subtype. The appearance of a new influenza A virus subtype is the first step toward a pandemic; however, to cause a pandemic, the new virus subtype also must have the capacity to spread easily from person to person. Once a new pandemic influenza virus emerges and spreads, it usually becomes established among people and moves around or “circulates” for many years as seasonal epidemics of influenza. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have large surveillance programs to monitor and detect influenza activity around the world, including the emergence of possible pandemic strains of influenza virus.

Influenza pandemics during the 20th century. During the 20th century, the emergence of several new influenza A virus subtypes caused three pandemics, all of which spread around the world within a year of being

detected. 1918-19, "Spanish flu," [A (H1N1)], caused the highest number of known influenza deaths. (However, the actual influenza virus subtype was not detected in the 1918-19 pandemic). More than 500,000 people died in the United States, and up to 50 million

people may have died worldwide. Many people died within the first few days after infection, and others died of secondary complications. Nearly half of those who died were young, healthy adults. Influenza A (H1N1) viruses still circulate today after being

introduced again into the human population in 1977. 1957-58, "Asian flu," [A (H2N2)], caused about 70,000 deaths in the United States.

First identified in China in late February 1957, the Asian flu spread to the United States by June 1957. 1968-69, "Hong Kong flu," [A (H3N2)], caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today. Both the 1957-58 and 1968-69 pandemics were caused by viruses containing a combination of

genes from a human influenza virus and an avian influenza virus. The 1918-19 pandemic virus appears to have an avian origin.

Preparing for the next influenza pandemic. Many scientists believe it is only a matter of time until the next influenza pandemic occurs. The severity of the next pandemic cannot be predicted, but modeling studies suggest that the impact of a pandemic on the United States could be substantial. In the absence of any control measures (vaccination or drugs), it has been estimated that

in the United States a “medium–level” pandemic could cause 89,000 to 207,000 deaths, 314,000 and 734,000 hospitalizations, 18 to 42 million outpatient visits, and another 20 to 47 million people being sick. Between 15% and 35% of the U.S. population could be affected by an influenza pandemic, and the economic impact could

range between $71.3 and $166.5 billion. Influenza pandemics are different from many of the threats for which public health and health-care systems are currently planning for a pandemic will last much longer than most public health emergencies and may

include “waves” of influenza activity separated by months (in 20th century pandemics, a second wave of influenza activity occurred 3 to 12 months after the first wave).

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The numbers of health-care workers and first responders available to work can be expected to be reduced. They will be at high risk of illness through exposure in the

community and in health-care settings, and some may have to miss work to care for ill family members. Resources in many locations could be limited, depending on the severity and spread of an influenza pandemic. Because of these differences and the expected size of an influenza pandemic, it is important to plan preparedness activities

that will permit a prompt and effective public health response. The U.S. Department of Health and Human Services (HHS) supports pandemic influenza activities in the areas of surveillance (detection), vaccine development and production, strategic stockpiling of antiviral medications, research, and risk communications. In May 2005, the U.S.

Secretary of HHS created a multi-agency National Influenza Pandemic Preparedness and Response Task Group. This unified initiative involves CDC and many other agencies (international, national, state, local and private) in planning for a potential

pandemic. Its responsibility includes revision of a U.S. National Pandemic Influenza Response and Preparedness Plan.

EVA-10: A botanical based, comprehensive treatment for avian influenza (H5N1) and viral infections in humans The lack of the pharmaceutical industry to adequately address and control the

emergence of the avian influenza (H5N1) underscores the need for a new comprehensive approach with quick approval times. EVA-10 major anti-viral component was shown to avian influenza infections by inhibiting H5N1 viral uptake

into cells. Other fractions have been shown to broadly inhibit viruses, bacteria, bacterial toxins and inflammatory cytokines, all important contributors to the pathology seen in humans with H5N1 infections. Given that there is no effective treatment available for avian influenza, EVA-10 treatment should be incorporated into

the clinical treatment protocol for patients infected with H5N1. Avian influenza, with its high case mortality rate and acquisition of genetic mutations leading toward efficient human to human transmission has become the single most

pressing health issue of our time. The virus responsible for avian influenza (H5N1), with its ability to adapt quickly to changing environmental conditions, has effectively evaded all counter-measures. Attempts by the pharmaceutical industry to provide an effective therapy against this viral “moving target” has proven futile and has left the

public vulnerable. Reliance on a single molecule drug paradigm coupled with a lengthy drug approval process is ultimately responsible for this failure. Drugs based on single molecules typically address one aspect of the viral life cycle which limits their effectiveness and leaves them susceptible to viral resistance. The proposed use of oseltamivir phosphate (Tamiflu) as a treatment for avian influenza is a

highly relevant example. While oseltamivir carboxylate (the active metabolite for oseltamivir phosphate) has been shown to inhibit Type A influenza viral release in cell cultures, it is not an effective treatment for influenza illness in humans. In essence, oseltamivir phosphate (Tamiflu) decreases the duration of influenza illness by about

one day, will not work if not administered within 48 hrs of infection, and is highly susceptible viral resistance. Many oseltamivir-treated patients with A/H5N1 disease have died (Hayden et al.,

2005) and a recent meta-analysis on the effectiveness of current influenza treatments could find no credible evidence of the effects of neuraminidase inhibitors on avian influenza (Jefferson et al., 2006). Oseltamivir resistant A/H5N1 has become more prevalent, most likely a result of incomplete viral suppression by the drug (de Jong et

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al., 2005). Furthermore, front line doctors in Vietnam have now concluded that the use of oseltamivir has not been an effective treatment. The ineffectiveness of

oseltamivir phosphate in humans and the propensity towards viral resistance is undoubtedly due to the fact that it is a single molecular entity directed at an inappropriate viral target (neuraminidase inhibition). The lack of the pharmaceutical industry to adequately address and control the emergence of avian influenza (H5N1) underscores the need for new anti-viral prevention and treatment strategies for emerging viral disease. In order to overcome

the inherent limitations of the pharmaceutical approach, therapies directed at emerging viral disease need to be comprehensive and be allowed a quick approval time. Rauthschild’s approach has been to combine non-toxic, anti-viral compounds, each directed at a specific component of the relevant viruses life cycle. A pharmaceutical drug version of this “cocktail” approach has been used against viruses such as HIV with reasonably good success. However, the inherent toxicities associated with these

drugs continue to be a major limiting factor for their practical use. To overcome this limitation, Rauthschild utilize anti-viral fractions isolated from botanical sources with well established safety profiles. Botanicals are excellent source materials as numerous plants contain highly effective anti-microbial defense molecules that are entirely safe

for human consumption. These anti-viral formulations are delivered as an oral liquid allowing fractional dosing, ease of administration, and rapid GI mucosal, GI luminal targets and systemic delivery of anti-viral components. EVA-10 was developed from Rauthschild’s influenza platform formulation which was designed to inhibit multiple components of the influenza viral life cycle (viral binding, uncoating, replication, and release). This platform has been shown to be highly effective at reducing the duration of influenza illness in humans. EVA-10 contains the potent anti-viral compound, EVA-10 (a proprietary theaflavin derivative) that has been shown to inhibit H5N1 viral infections by blocking the uptake of the virus into cells. EVA-10 has also been shown to inhibit replication of SARS CoV and a crude fraction was shown to inhibit the 3C-like protease encoded by SARS-CoV. Secondary bacterial infections are commonplace in influenza illness and are a major cause of mortality. EVA-10 fractions inhibit clinically important bacteria such as

Escherichia coli O157: H7 (EHEC), Staphylococcus aureus, Streptococcus mutans, Vibrio cholerae and Pseudomonas aeruginosa (Amarowicz et al., 2000; Bandyopadhyay et al., 2005; Dell'Aica et al., 2004; Hamilton-Miller et al., 1999; Limsong et al., 2004; Tegos et al., 2002; Tiwari et al., 2005). EVA-10 also inactivates secreted bacterial

toxins such as anthrax lethal factor (LF), Vero toxins (VTs) from enterohemorrhagic Escherichia coli (EHEC), botulinum neurotoxin and tetanus toxin (Choudhary et al., 2005; Dell'Aica et al., 2004; 2003; Di Paola et al., 2005; Kagaya et al., 2002; Okubo et al., 1998; Qin et al., 1997; Qin et al., 2000; Satoh et al., 2001; Satoh et al., 2001;

Satoh et al., 2002; Satoh et al., 2002; Sawamura et al., 2002; Sugita-Konishi et al., 1999; Tombola et al., 2003).

Cytokine storms develop in avian influenza patients and is the reason why avian influenza is so deadly. EVA-10 inhibits production and release of inflammatory cytokines (TNF-Alpha, interleukin-1beta, and interleukin-6) in alveolar macrophages involving nuclear factor-kappa B dependent and independent mechanisms (Aktas et

al., 2004; Aneja et al., 2004; Birrell et al., 2005; Chan et al., 1997; Chen et al., Cho et al., 2002; Crouvezier et al., 2001; Culpitt et al., 2003; Donnelly et al., 2004; Lin et al., 1997; 2002; Lin at al., 1999; Lin et al., 1999; Manna SK., et al., 2000; Marier et

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al., 2005; Nomura et al., 2000; Pan et al., 2000; Pan et al., 2000; Tsai et al.,1999; Wheeler et al., 2004; Yang et al., 1998; Yang et al., 2001).

Even though EVA-10 is a relatively new medicine, components of the EVA-10 complex components have excellent clinical records and are classified by the U.S. FDA as GRAS (Generally Regarded As Safe). EVA-10 components were widely used as a

preventative measure against Severe Acute Respiratory Syndrome (SARS) by attending physicians and nurses at the SARS designated hospital in Taiwan. Two nurses, each infected with SARS, received components of EVA-10 for treatment and the illness resolved within 48 hours of treatment. 2006). Components of EVA-10

complex are used to effectively treat a wide range of viral and bacterial diseases and is currently used to control pulmonary fluid buildup in Mesothelioma, SV-40 and lung cancer patients. By combining EVA-10 with amyloxine treatment protocols, the lung

tissue destruction normally seen in these patients is abated. Given the safety profile and potential as a treatment for avian influenza illness, EVA-10

is an excellent choice for incorporation in hospital clinical protocols for patients with avian influenza illness.

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