Rauthschild’s EVA-10 COMPLEX


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Rauthschild’s EVA-10 COMPLEX

  1. 1. Rauthschild’s EVA-10 ComplexResearch and DevelopmentOur research and development focus is on viral and neoplastic disease. Our basicresearch 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 researchinstitutes 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 itsagricultural-based communities and high population density, Rauthschild’s haspositioned itself on the front line of this by synthesizing the collective body of scientificand medical research literature to create the most advance botanical anti- viral andanti-cancer product research in the world. Based on the most current clinical findingsfrom our worldwide network, Rauthschild’s Research Group is responsible for thedevelopment of a broad spectrum platform technology that has proven to havedownstream applications for SARS, Influenza, Herpes, HIV, Bird Flu (H5N1) andcancer. Results from multi-center study showed our platform to be effective ininactivating SARS CoV, Staphylococcus aureus, Steptococcus pneumonia, humaninfluenza (H3N2), and bird flu (H5N1) and is the source material for the developmentof our ethical pharmaceutical drug candidates.The traditional pharmaceutical paradigm does not work foremerging viral diseaseWe are living in an age where the phrase "emerging virus" has taken its place in ourgeneral vernacular. Emerging viruses such as SARS CoV, and H5N1 have taken worldstage in terms of posing significant threats to humanity. Why then, are we not able toeffectively combat these viruses? The answer is buried in the very essence of theexisting 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. Ingeneral, this process takes from 5 to 10 years. While this paradigm produces effectivedrugs for diseases such as arthritis and diabetes, it does not work for diseases causedby emerging viruses. Under the existing pharmaceutical/FDA paradigm, once a newvirus emerges, there are essentially two options. The first option is to use outdatedanti-viral drugs (outdated in the sense that they were developed years earlier fordifferent viruses) and just hope that something works. The second option is to spendthe next 5 to 10 years developing a new drug that will ultimately be too late to savecountless lives. Neither option works for emerging viruses. The SARS outbreak is aperfect example. The standard treatment protocol was to use ribavarin and steroidcombination therapy. This was not only ineffective but ultimately caused severe andpermanent damage to many patients "lucky" enough to survive the illness. We arenow facing a similar but much larger problem with Bird Flu. A second problem with thetraditional pharmaceutical approach, concerns the use of synthetic molecules designedto target one aspect of disease. Again, this approach may be useful for "gardenvariety" disease but fails when it comes to viral disease. Viruses are not static andthey are constantly mutating and changing the "therapeutic targets". This leads todrug resistance and the drug quickly become ineffective. 1
  2. 2. The comprehensive approachOur approach has been to combine non-toxic, anti-viral compounds, each directed at aspecific component of the relevant viruses life cycle. A pharmaceutical drug version ofthis “cocktail” approach has been used against viruses such as HIV with reasonablygood success. However, the inherent toxicities associated with these drugs continueto 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 numerousplants contain highly effective anti-microbial defense molecules that are entirely safefor human consumption. These anti-viral formulations are delivered as an oral liquidallowing fractional dosing, ease of administration, and rapid GI mucosal, GI luminaltargets and systemic delivery of anti-viral components.EVA-10 is Rauthschild’s proprietary broad spectrum anti-microbial anti-viral platformtechnology. Components of EVA-10 have been characterized in multi-center, anti- viralprojects. Broad in its effectiveness against microbes suggesting its ant-viral target is avery ancient and highly conserved feature of microbes. Therefore, it follows that it isunlikely that viruses and bacteria will be able to develop resistance against EVA-10.EVA10 – RAUTHSCHILD NEW DRUG EVA-10 COMPLEX CANDIDATES FORTHE TREATMENT OF AVIAN INFLUENZA, HERPES, HIV, SARS ANDCERTAIN NEOPLASIAEVA-10 is composed of four theaflavin isomers (EVA-10a-c). These are only are someof the major components of the complex Rauthschild utilizes for the treatment andprevention of AVIAN INFLUENZA and other viral disease.This mixture of these molecules (EVA-10a-c) is extremely effective at inhibiting thereplication of SARS CoV in Vera cells. Recently, EVA-10b and EVA-10c we bothshown to strongly inhibit the SARS-CoV 3C-like Protease Activity (Chen et al., EvidBased Complement Alternat Med. 2005 Jun;2(2):209-215). The IC (50) was 7 microMand 9.5 microM respectively.The virally encoded 3C-like protease (3CLPro) is critical for the viral replication ofSARS-CoV in infected host cells and is one of the most promising targets for anti-SARS-CoV drugsEVA-10a, EVA-10bb and EVA-10C each inhibits the infectivity of H5N1 virus in MDCKcells. 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. 2
  3. 3. Emerging VirusesAfter a century of prevention and control efforts, infectious disease remains the mostproblematic public health and global destabilizing issue facing mankind. Insidious bynature, infectious disease directly causes 13 million deaths and contributes to thedeath of many millions annually. These numbers are increasing as a direct result ofglobal economic, technology, environmental degradation and environmentmicroorganism interaction. Synergistic interplay of these parameters drive theemergence of new diseases, the re-emergence of diseases once controlled, and thedevelopment of antimicrobial resistanceOur biologic world is not static. The concept of “emerging infectious diseases”appeared in the late 1980s, when major disease outbreaks occurred around the globeand surprised many scientists who considered infectious diseases to be maladies of thepast or limited to the under-developed regions of the world. Viruses, especially RNAviruses, with their ability to adapt quickly to changing environmental conditions, areamong the most prominent causes of emerging infectious diseases. Nearly all of theseemergent disease episodes have involved zoonotic or species- jumping infectiousagents. New viral zoonotic diseases, such as acquired immune deficiency syndrome(AIDS), caused by human immunodeficiency viruses 1 or 2, emerged in the 1980s and1990s, and have become established in the human population. Influenza viruscontinues to find new ways to move from avian species into humans. The filovirusesand the newer paramyxo viruses, Hendra and Nipah, highlight the increasing proclivityof some animal viral agents to infect human populations with devastating results. Apreviously unknown transmissible spongiform encephalopathy, bovine spongiformencephalopathy, has emerged in cattle in Europe and spread to humans as well asother animal species. Emerging viruses usually have identifiable sources, often existingviruses of animals or humans that have been given opportunities to infect new hostpopulations ("viral traffic"). The reservoirs are often infected subclinically orasymptomatically and the distribution of the diseases reflects the range and thepopulation dynamics of their reservoir hosts. In addition, bioterrorism has become animportant factor which must now also be considered in infectious diseaseemergence/re-emergence.Extensive outbreaks of zoonotic disease are not uncommon, especially as the diseaseis often not recognized as zoonotic at the outset and may spread undetected for sometime.Environmental and social changes, frequently the result of human activities, canaccelerate viral traffic, with consequent increases in disease emergence. The complexinteraction of factors, such as environmental and ecological changes, social factors,decline of health care, human demographics and behavior, influences the emergenceor re-emergence of such diseases. Increasing numbers of emerging viral diseaseepisodes seem to be linked to a decline in global resources for proven public healthprograms, agricultural extension programs, and the like, programs that have stood inthe way of the spread and evolution of viral pathogens. These factors, combined withthe ongoing evolution of viral and microbial variants, make it likely that emerginginfections will continue to appear and probably increase. 3
  4. 4. InfluenzaEpidemics of influenza typically occur during the winter months in temperate regionsand have been responsible for an average of approximately 36,000 deaths/year in theUnited States during 1990–1999. Influenza viruses also can cause pandemics, duringwhich rates of illness and death from influenza-related complications can increaseworldwide. Influenza viruses cause disease among all age groups. Rates of infectionare highest among children, but rates of serious illness and death are highest amongpersons aged > 65 years, children aged <2 years, and persons of any age who havemedical conditions that place them at increased risk for complications from influenza.Influenza vaccination is the primary method for preventing influenza and its severecomplications. In this report from the Advisory Committee on Immunization Practices(ACIP), the primary target groups recommended for annual vaccination are 1) personsat 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 certainchronic medical conditions); 2) persons aged 50--64 years because this group has anelevated prevalence of certain chronic medical conditions; and 3) persons who livewith or care for persons at high risk (e.g., health-care workers and household contactswho have frequent contact with persons at high risk and who can transmit influenza tothose persons at high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalizationand death among persons at high risk, otitis media among children, and workabsenteeism among adults. Although influenza vaccination levels increasedsubstantially during the 1990s, further improvements in vaccine coverage levels areneeded, chiefly among persons aged <65 years who are at increased risk for influenza-related complications among all racial and ethnic groups, among blacks and Hispanicsaged > 65 years, among children aged 6–23 months, and among health-care workers.ACIP recommends using strategies to improve vaccination levels, including usingreminder/recall systems and standing orders programs. Although influenza vaccinationremains the cornerstone for the control and treatment of influenza, information onantiviral 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 humandisease. Influenza A viruses are further categorized into subtypes on the basis of twosurface antigens: hemagglutinin and neuraminidase. Influenza B viruses are notcategorized 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 virusesare further separated into groups on the basis of antigenic characteristics. Newinfluenza virus variants result from frequent antigenic change (i.e., antigenic drift)resulting from point mutations that occur during viral replication. Influenza B virusesundergo antigenic drift less rapidly than influenza A viruses.Immunity to the surface antigens, particularly the hemagglutinin, reduces thelikelihood of infection and severity of disease if infection occurs. Antibody against oneinfluenza virus type or subtype confers limited or no protection against another type orsubtype of influenza. Furthermore, antibody to one antigenic variant of influenza virusmight not completely protect against a new antigenic variant of the same type orsubtype. Frequent development of antigenic variants through antigenic drift is the 4
  5. 5. virologic basis for seasonal epidemics and the reason for the usual incorporation of oneor more new strains in each years influenza vaccine.Clinical signs and symptoms of influenza.Influenza viruses are spread from person to person primarily through the coughingand sneezing of infected persons. The typical incubation period for influenza is 1–4days, with an average of 2 days. Adults can be infectious from the day beforesymptoms begin through approximately 5 days after illness onset. Children can beinfectious for > 10 days, and young children can shed virus for several days beforetheir illness onset. Severely immune compromised persons can shed virus for weeks ormonths.Uncomplicated influenza illness is characterized by the abrupt onset of constitutionaland 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 illnesscaused by influenza is difficult to distinguish from illness caused by other respiratorypathogens on the basis of symptoms alone. Reported sensitivities and specificities ofclinical definitions for influenza-like illness (ILI) in studies primarily among adults thatinclude fever and cough have ranged from 63% to 78% and 55% to 71%,respectively, compared with viral culture. Sensitivity and predictive value of clinicaldefinitions can vary, depending on the degree of co-circulation of other respiratorypathogens and the level of influenza activity. A study among older nonhospitalizedpatients determined that symptoms of fever, cough, and acute onset had a positivepredictive value of 30% for influenza, whereas a study of hospitalized older patientswith chronic cardiopulmonary disease determined that a combination of fever, cough,and illness of <7 days was 78% sensitive and 73% specific for influenza). However, astudy among vaccinated older persons with chronic lung disease reported that coughwas not predictive of influenza infection, although having a fever or feverishness was68% sensitive and 54% specific for influenza infection.Influenza illness typically resolves after 3–7 days for the majority of persons, althoughcough and malaise can persist for >2 weeks. Among certain persons, influenza canexacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead tosecondary bacterial pneumonia or primary influenza viral pneumonia, or occur as partof a coinfection with other viral or bacterial pathogens. Young children with influenzainfection can have initial symptoms mimicking bacterial sepsis with high fevers, and <20% of children hospitalized with influenza can have febrile seizures. Influenzainfection has also been associated with encephalopathy, transverse myelitis, Reyesyndrome, myositis, myocarditis, and pericarditis.Hospitalizations and deaths from influenza.The risks for complications, hospitalizations, and deaths from influenza are higheramong persons aged > 65 years, young children, and persons of any age with certainunderlying health conditions (see Persons at Increased Risk for Complications) thanamong healthy older children and younger adults). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conductedduring different influenza epidemics. 5
  6. 6. Among children aged 0–4 years, hospitalization rates have ranged from approximately500/100,000 children for those with high-risk medical conditions to 100/100,000children 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 comparableto rates reported among persons aged > 65 years.During influenza epidemics from 1979–80 through 2000–01, the estimated overallnumber of influenza-associated hospitalizations in the United States ranged fromapproximately 54,000 to 430,000/epidemic. An average of approximately 226,000influenza-related excess hospitalizations occurred per year, with 63% of allhospitalizations occurring among persons aged > 65 years. Since the 1968 influenza A(H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizationshave occurred during epidemics caused by type A (H3N2) viruses. Influenza-relateddeaths can result from pneumonia and from exacerbations of cardiopulmonaryconditions and other chronic diseases. Deaths of older adults account for > 90% ofdeaths attributed to pneumonia and influenza. In one study of influenza epidemics,approximately 19,000 influenza-associated pulmonary and circulatory deaths perinfluenza season occurred during 1976–1990, compared with approximately 36,000deaths during 1990--1999. Estimated rates of influenza- associated pulmonary andcirculatory 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. Inthe United States, the number of influenza-associated deaths might be increasing inpart because the number of older persons is increasing. In addition, influenza seasonsin 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- riskconditions, but do occur). A study that modeled influenza-related deaths estimatedthat an average of 92 deaths (0.4 deaths per 100,000) occurred among children aged<5 years annually during the 1990s, compared with 32,651 deaths (98.3 per100,000) among adults aged > 65 years. Reports of 153 laboratory- confirmedinfluenza-related pediatric deaths from 40 states during the 2003–04 influenza seasonindicated 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 aperson at risk for influenza-related complications (CDC, National Center for InfectiousDiseases, unpublished data, 2005). Further information is needed regarding the riskfor severe influenza-complications and optimal strategies for minimizing severedisease and death among children.Avian Influenza (H5N1)Avian influenza in birds.Avian influenza is an infection caused by avian (bird) influenza (flu) viruses. Theseinfluenza viruses occur naturally among birds. Wild birds worldwide carry the viruses intheir intestines, but usually do not get sick from them. However, avian influenza isvery contagious among birds and can make some domesticated birds, includingchickens, ducks, and turkeys, very sick and kill them. Infected birds shed influenzavirus in their saliva, nasal secretions, and feces. Susceptible birds become infectedwhen they have contact with contaminated secretions or excretions or with surfacesthat are contaminated with secretions or excretions from infected birds. Domesticatedbirds may become infected with avian influenza virus through direct contact withinfected waterfowl or other infected poultry, or through contact with surfaces (such asdirt or cages) or materials (such as water or feed) that have been contaminated with 6
  7. 7. the virus.Infection with avian influenza viruses in domestic poultry causes two main forms ofdisease that are distinguished by low and high extremes of virulence. The “lowpathogenic” form may go undetected and usually causes only mild symptoms (such asruffled feathers and a drop in egg production). However, the highly pathogenic formspreads more rapidly through flocks of poultry. This form may cause disease thataffects 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 differbecause of changes in certain proteins on the surface of the influenza A virus(hemagglutinin [HA] and neuraminidase [NA] proteins). There are 16 known HAsubtypes and 9 known NA subtypes of influenza A viruses. Many different combinationsof 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, “avianinfluenza virus” refers to influenza A viruses found chiefly in birds, but infections withthese viruses can occur in humans. The risk from avian influenza is generally low tomost people, because the viruses do not usually infect humans. However, confirmedcases of human infection from several subtypes of avian influenza infection have beenreported since 1997. Most cases of avian influenza infection in humans have resultedfrom contact with infected poultry (e.g., domesticated chicken, ducks, and turkeys) orsurfaces contaminated with secretion/excretions from infected birds. The spread ofavian 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 amonghumans. There are only three known A subtypes of influenza viruses (H1N1, H1N2 andH3N2) currently circulating among humans. It is likely that some genetic parts ofcurrent human influenza A viruses came from birds originally. Influenza A viruses areconstantly changing, and they might adapt over time to infect and spread amonghumans.During an outbreak of avian influenza among poultry, there is a possible risk to peoplewho have contact with infected birds or surfaces that have been contaminated withsecretions or excretions from infected birds. Symptoms of avian influenza in humanshave ranged from typical human influenza- like symptoms (e.g., fever, cough, sorethroat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases(such as acute respiratory distress), and other severe and life-threateningcomplications. The symptoms of avian influenza may depend on which virus causedthe infection.Avian influenza A (H5N1).Influenza A (H5N1) virus – also called “H5N1 virus” – is an influenza A virus subtypethat occurs mainly in birds, is highly contagious among birds, and can be deadly tothem. Outbreaks of avian influenza H5N1 occurred among poultry in eight countries inAsia (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 theaffected countries either died from the disease or were killed in order to try to control 7
  8. 8. the outbreaks. By March 2004, the outbreak was reported to be under control. Sincelate June 2004, however, new outbreaks of influenza H5N1 among poultry werereported by several countries in Asia (Cambodia, China [Tibet], Indonesia, Kazakhstan,Malaysia, Mongolia, Russia [Siberia], Thailand, and Vietnam). It is believed that theseoutbreaks are ongoing. Influenza H5N1 infection also has been reported among poultryin Turkey Romania, and Ukraine. Outbreaks of influenza H5N1 have been reportedamong wild migratory birds in China, Croatia, Mongolia, and Romania. Human casesof 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 beenreported by the World Health Organization since January 2004. Most of these caseshave occurred as a result of people having direct or close contact with infected poultryor contaminated surfaces; however, a few cases of human-to-human spread of H5N1have occurred.Of the few avian influenza viruses that have crossed the species barrier to infecthumans, H5N1 has caused the largest number of detected cases of severe disease anddeath in humans. In the current outbreaks in Asia and Europe, more than half of thoseinfected with the virus have died. Most cases have occurred in previously healthychildren and young adults. However, it is possible that the only cases currently beingreported are those in the most severely ill people, and that the full range of illnesscaused 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 notcontinued beyond one person. Nonetheless, because all influenza viruses have theability to change, scientists are concerned that H5N1 virus one day could be able toinfect humans and spread easily from one person to another. Because these viruses donot commonly infect humans, there is little or no immune protection against them inthe human population. If H5N1 virus were to gain the capacity to spread easily fromperson to person, an influenza pandemic (worldwide outbreak of disease) could begin.An influenza pandemic is a global outbreak of disease that occurs when a newinfluenza A virus appears or “emerges” in the human population, causes seriousillness, and then spreads easily from person to person worldwide. Pandemics aredifferent from seasonal outbreaks or “epidemics” of influenza. Seasonal outbreaks arecaused by subtypes of influenza viruses that already circulate among people, whereaspandemic outbreaks are caused by new subtypes, by subtypes that have nevercirculated among people, or by subtypes that have not circulated among people for along time. Past influenza pandemics have led to high levels of illness, death, socialdisruption, and economic loss.Emergence of Pandemic Influenza viruses.There are many different subtypes of Influenza or “flu” viruses. The subtypes differbased 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 causesan abrupt or sudden, major change in influenza A viruses. These changes are causedby new combinations of the HA and/or NA proteins on the surface of the virus. Such 8
  9. 9. changes result in a new influenza A virus subtype. The appearance of a new influenzaA 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 toperson. Once a new pandemic influenza virus emerges and spreads, it usually becomesestablished among people and moves around or “circulates” for many years asseasonal epidemics of influenza. The U.S. Centers for Disease Control and Prevention(CDC) and the World Health Organization (WHO) have large surveillance programs tomonitor and detect influenza activity around the world, including the emergence ofpossible pandemic strains of influenza virus.Influenza pandemics during the 20th century.During the 20th century, the emergence of several new influenza A virus subtypescaused three pandemics, all of which spread around the world within a year of beingdetected.1918-19, "Spanish flu," [A (H1N1)], caused the highest number of known influenzadeaths. (However, the actual influenza virus subtype was not detected in the 1918-19pandemic). More than 500,000 people died in the United States, and up to 50 millionpeople may have died worldwide. Many people died within the first few days afterinfection, and others died of secondary complications. Nearly half of those who diedwere young, healthy adults. Influenza A (H1N1) viruses still circulate today after beingintroduced 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 Statesby June 1957.1968-69, "Hong Kong flu," [A (H3N2)], caused about 34,000 deaths in the UnitedStates. This virus was first detected in Hong Kong in early 1968 and spread to theUnited States later that year. Influenza A (H3N2) viruses still circulate today. Both the1957-58 and 1968-69 pandemics were caused by viruses containing a combination ofgenes from a human influenza virus and an avian influenza virus. The 1918-19pandemic 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 pandemicoccurs. The severity of the next pandemic cannot be predicted, but modeling studiessuggest that the impact of a pandemic on the United States could be substantial. Inthe absence of any control measures (vaccination or drugs), it has been estimated thatin the United States a “medium–level” pandemic could cause 89,000 to 207,000deaths, 314,000 and 734,000 hospitalizations, 18 to 42 million outpatient visits, andanother 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 couldrange between $71.3 and $166.5 billion. Influenza pandemics are different from manyof the threats for which public health and health-care systems are currently planningfor a pandemic will last much longer than most public health emergencies and mayinclude “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). 9
  10. 10. The numbers of health-care workers and first responders available to work can beexpected to be reduced. They will be at high risk of illness through exposure in thecommunity and in health-care settings, and some may have to miss work to care for illfamily members. Resources in many locations could be limited, depending on theseverity and spread of an influenza pandemic. Because of these differences and theexpected size of an influenza pandemic, it is important to plan preparedness activitiesthat will permit a prompt and effective public health response. The U.S. Department ofHealth and Human Services (HHS) supports pandemic influenza activities in the areasof surveillance (detection), vaccine development and production, strategic stockpilingof antiviral medications, research, and risk communications. In May 2005, the U.S.Secretary of HHS created a multi-agency National Influenza Pandemic Preparednessand Response Task Group. This unified initiative involves CDC and many otheragencies (international, national, state, local and private) in planning for a potentialpandemic. Its responsibility includes revision of a U.S. National Pandemic InfluenzaResponse and Preparedness Plan.EVA-10: A botanical based, comprehensive treatment for avianinfluenza (H5N1) and viral infections in humansThe lack of the pharmaceutical industry to adequately address and control theemergence of the avian influenza (H5N1) underscores the need for a newcomprehensive approach with quick approval times. EVA-10 major anti-viralcomponent was shown to avian influenza infections by inhibiting H5N1 viral uptakeinto cells. Other fractions have been shown to broadly inhibit viruses, bacteria,bacterial toxins and inflammatory cytokines, all important contributors to thepathology seen in humans with H5N1 infections. Given that there is no effectivetreatment available for avian influenza, EVA-10 treatment should be incorporated intothe clinical treatment protocol for patients infected with H5N1.Avian influenza, with its high case mortality rate and acquisition of genetic mutationsleading toward efficient human to human transmission has become the single mostpressing health issue of our time. The virus responsible for avian influenza (H5N1),with its ability to adapt quickly to changing environmental conditions, has effectivelyevaded all counter-measures. Attempts by the pharmaceutical industry to provide aneffective therapy against this viral “moving target” has proven futile and has left thepublic vulnerable. Reliance on a single molecule drug paradigm coupled with a lengthydrug approval process is ultimately responsible for this failure.Drugs based on single molecules typically address one aspect of the viral life cyclewhich limits their effectiveness and leaves them susceptible to viral resistance. Theproposed use of oseltamivir phosphate (Tamiflu) as a treatment for avian influenza is ahighly relevant example. While oseltamivir carboxylate (the active metabolite foroseltamivir phosphate) has been shown to inhibit Type A influenza viral release in cellcultures, it is not an effective treatment for influenza illness in humans. In essence,oseltamivir phosphate (Tamiflu) decreases the duration of influenza illness by aboutone day, will not work if not administered within 48 hrs of infection, and is highlysusceptible 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 treatmentscould find no credible evidence of the effects of neuraminidase inhibitors on avianinfluenza (Jefferson et al., 2006). Oseltamivir resistant A/H5N1 has become moreprevalent, most likely a result of incomplete viral suppression by the drug (de Jong et 10
  11. 11. al., 2005). Furthermore, front line doctors in Vietnam have now concluded that theuse of oseltamivir has not been an effective treatment. The ineffectiveness ofoseltamivir phosphate in humans and the propensity towards viral resistance isundoubtedly due to the fact that it is a single molecular entity directed at aninappropriate viral target (neuraminidase inhibition).The lack of the pharmaceutical industry to adequately address and control theemergence of avian influenza (H5N1) underscores the need for new anti-viralprevention and treatment strategies for emerging viral disease. In order to overcomethe inherent limitations of the pharmaceutical approach, therapies directed atemerging viral disease need to be comprehensive and be allowed a quick approvaltime.Rauthschild’s approach has been to combine non-toxic, anti-viral compounds, eachdirected at a specific component of the relevant viruses life cycle. A pharmaceuticaldrug version of this “cocktail” approach has been used against viruses such as HIVwith reasonably good success. However, the inherent toxicities associated with thesedrugs continue to be a major limiting factor for their practical use. To overcome thislimitation, Rauthschild utilize anti-viral fractions isolated from botanical sources withwell established safety profiles. Botanicals are excellent source materials as numerousplants contain highly effective anti-microbial defense molecules that are entirely safefor human consumption. These anti-viral formulations are delivered as an oral liquidallowing fractional dosing, ease of administration, and rapid GI mucosal, GI luminaltargets and systemic delivery of anti-viral components.EVA-10 was developed from Rauthschild’s influenza platform formulation which wasdesigned to inhibit multiple components of the influenza viral life cycle (viral binding,uncoating, replication, and release). This platform has been shown to be highlyeffective at reducing the duration of influenza illness in humans. EVA-10 contains thepotent anti-viral compound, EVA-10 (a proprietary theaflavin derivative) that has beenshown 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 fractionwas shown to inhibit the 3C-like protease encoded by SARS-CoV.Secondary bacterial infections are commonplace in influenza illness and are a majorcause of mortality. EVA-10 fractions inhibit clinically important bacteria such asEscherichia coli O157: H7 (EHEC), Staphylococcus aureus, Streptococcus mutans,Vibrio cholerae and Pseudomonas aeruginosa (Amarowicz et al., 2000; Bandyopadhyayet al., 2005; DellAica 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 bacterialtoxins such as anthrax lethal factor (LF), Vero toxins (VTs) from enterohemorrhagicEscherichia coli (EHEC), botulinum neurotoxin and tetanus toxin (Choudhary et al.,2005; DellAica et al., 2004; 2003; Di Paola et al., 2005; Kagaya et al., 2002; Okuboet 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 avianinfluenza is so deadly. EVA-10 inhibits production and release of inflammatorycytokines (TNF-Alpha, interleukin-1beta, and interleukin-6) in alveolar macrophagesinvolving nuclear factor-kappa B dependent and independent mechanisms (Aktas etal., 2004; Aneja et al., 2004; Birrell et al., 2005; Chan et al., 1997; Chen et al., Choet al., 2002; Crouvezier et al., 2001; Culpitt et al., 2003; Donnelly et al., 2004; Lin etal., 1997; 2002; Lin at al., 1999; Lin et al., 1999; Manna SK., et al., 2000; Marier et 11
  12. 12. 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 complexcomponents 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 apreventative measure against Severe Acute Respiratory Syndrome (SARS) byattending physicians and nurses at the SARS designated hospital in Taiwan. Twonurses, each infected with SARS, received components of EVA-10 for treatment andthe illness resolved within 48 hours of treatment. 2006). Components of EVA-10complex are used to effectively treat a wide range of viral and bacterial diseases and iscurrently used to control pulmonary fluid buildup in Mesothelioma, SV-40 and lungcancer patients. By combining EVA-10 with amyloxine treatment protocols, the lungtissue destruction normally seen in these patients is abated.Given the safety profile and potential as a treatment for avian influenza illness, EVA-10is an excellent choice for incorporation in hospital clinical protocols for patients withavian influenza illness.REFERENCESAktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel PM,Infante-Duarte C, Brocke S, Zipp F. J Immunol. 2004 Nov 1;173(9):5794-800.Amarowicz R, Pegg RB, Bautista DA. Nahrung. 2000 Feb;44(1):60-2Aneja R, Odoms K, Denenberg AG, Wong HR. Crit Care Med. 2004 Oct;32(10):2097-103.Bandyopadhyay D, Chatterjee TK, Dasgupta A, Lourduraja J, Dastidar SG. Biol PharmBull. 2005 Nov;28(11):2125-7Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. FASEB J. 2005May;19(7):840-1. Epub 2005 Feb 25.Chan MM, Fong D, Ho CT, Huang HI. Biochem Pharmacol. 1997 Dec 15;54(12):1281-6.Chen PC, Wheeler DS, Malhotra V, Odoms K, Denenberg AG, Wong HR. Inflammation.2002 Oct;26(5):233-41.Cho DI, Koo NY, Chung WJ, Kim TS, Ryu SY, Im SY, Kim KM. Life Sci. 2002 Sep13;71(17):2071-82.Choudhary A, Verma RJ. Food Chem Toxicol. 2005 Jan;43(1):99-104. Crouvezier S, 12
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  15. 15. Tombola F, Campello S, De Luca L, Ruggiero P, Del Giudice G, Papini E, Zoratti M.:FEBS Lett. 2003 May 22;543(1-3):184-9Tsai SH, Lin-Shiau SY, Lin JK. Br J Pharmacol. 1999 Feb;126(3):673-80. Yang F, deVilliers WJ, McClain CJ, Varilek GW. J Nutr. 1998 Dec;128(12):2334-40. Yang F, Oz HS, Barve S, deVilliers WJ, McClain CJ, Varilek GW. Mol Pharmacol. 2001 Sep;60(3):528-33.Wheeler DS, Catravas JD, Odoms K, Denenberg A, Malhotra V, Wong HR. J Nutr. 2004May;134(5):1039-44.Manufactured By:Rauthschild’s Pharmaceutical, Inc.P.O. Box 30505Seattle, Washington 98133-0505 USASKYPE: ErnestRauthschild 15