AU2016100033A4

AU2016100033A4 - Biopharmaceutical with antiviral activity.

Info

Publication number: AU2016100033A4
Application number: AU2016100033A
Authority: AU
Inventors: Ruth Kendon
Original assignee: Rapid Nutrition Science Pty Ltd
Current assignee: Rapid Nutrition Science Pty Ltd
Priority date: 2015-01-28
Filing date: 2016-01-14
Publication date: 2016-02-11
Anticipated expiration: 2024-01-14

Abstract

Phytopharmaceutical application for antiviral effects. Abstract: The Invention is a phytochemical and biopharmaceutical composition for broad spectrum prevention, treatment and relief of viral infections including, but not limited to influenza, coronavirus, herpes and the common cold; in humans and animals.

Description

EDITORIAL NOTE 2016100033 - There are 11 pages of Description the last page should be numbered "11" Phytopharmaceutical application for antiviral effects. Field of the Invention: This Invention relates to the use of a combination of botanical substances which provide a broad spectrum of protection against, treatment of, and relief from acute respiratory viral infections, including, but not limited to influenza, SARS, MERS, Herpes and the common cold in humans and animals. Background to the Invention: The human cost of the problem. Influenza, SARS, MERS and common cold are all acute respiratory illnesses caused by viral infection. The cost of these infections may be measured in deaths, time off work, loss of well being and productivity. In Australia alone, according to government data, influenza affects 5-15% of the population; causes 1500-2500 deaths; 15,000 hospitalisations; and 80,000 visits to GPs each year. 10% of all illness-related absenteeism is due to influenza. According to WHO, influenza infects 10-20% of the population. In the USA this leads to 40-50,000 deaths; 150,000 hospitalisations; and 25-50 million cases per annum. This has been extrapolated to worldwide estimates of 1 billion cases of influenza, 3-5 million cases of severe illness, and 300-500,000 deaths annually. The common cold is a milder form of illness, lasting approximately a week, caused by any one of over 200 viruses. These are the most common cause of absenteeism, the most common cause of visits to GPs, and the most common contagious illness. 50% of the population of Australia catch colds in winter, and 25% in spring. Young children, their parents and their teachers catch about 6 colds per year, while school children and hospital workers catch from 6-12 colds per year. Adults without regular contact with children catch 2-3 colds annually. If we accept that 15% of the adult population catch influenza each year, and are unwell for 10 days each time, then an average person can expect to have flu 12 times in a life and lose up to 160 days experiencing symptoms. People in front line contact with the public may experience significantly worse. Time and productivity losses due to the common cold add to these figures significantly. The problem of rapid transmission. Acute Respiratory Viral Infections (ARVI's) are highly contagious; they are rapidly spread by mucus droplets in the air, produced by coughing and sneezing. They may survive up to 24 hours on external surfaces, where they can be further spread via surface to hand to mouth contact. Contagious viruses are most easily transmitted between persons in enclosed spaces, such as workplaces, classrooms and public transport. Persons travelling in passenger aircraft, where large numbers of people are confined in close proximity, breathing partially recirculated air, for many hours at a stretch - and with practical constraints on hand washing - are at particular risk. Contagious viruses are easily transported from country to country owing to the large numbers of people flying internationally for business and pleasure. As a result a traveller could be exposed to any number and variation of viruses from anywhere in the world. 1 ARVI's evolve rapidly, due to frequent errors in replication (genetic drift) and regular re arrangement of the viral envelope (genetic shift) giving rise to frequent mutations. These variants are immune to pre-existing (and highly specific) antibodies and vaccines. As a result vaccines and prior exposure give little or no protection against new strains, thus a broad spectrum preventive is needed. An example of this is SARS, or Sudden Acute Respiratory Syndrome. This is a virulent pneumonia due to a new and hitherto unknown variant of Coronavirus which appeared suddenly in Guangdong, China at the end of November 2002. Before it was contained in July 2003, it had spread to 32 countries, caused 8500 infections, and killed 813 people. These illness have a high economic and social cost, and effective prevention and treatment is needed. Prior art solutions: current treatments and their limitations 1. Vaccines Vaccines, the standard preventive therapy, work by challenging the immune system to produce antibodies against a virus or group of viruses. As in naturally-acquired immunity, this process takes up to 2 weeks for effective protection. - Vaccines are by their nature strain-specific. Even the newer combination vaccines are only helpful against known strains, and cannot protect against entirely new strains of virus. - Vaccines require up to 14 days to produce immunity, so that by the time a person has been exposed to infection, it is too late for effective prophylaxis. - Vaccines do not address the complications of inflammation and organ failure. 2. Antiviral medications Prescription antivirals block a single stage of viral activity, that is, the binding of the neuraminidase enzyme to cell membranes. - In the prophylaxis of influenza, neuraminidase inhibitors are only 35-75% effective. - As a treatment for symptomatic influenza, they are 61-73% effective. - They are unproven against SARS or the common cold. - They frequently produce side effects. - Their manufacture is costly and time-consuming. - The antiviral drugs fail to suppress inflammation. Other limitations of these two major medications can be divided broadly into two headings: (i) Side effects and (ii) Development of Drug Resistance (i) Side effects - Oseltamivir (Tamiflu) and Zanamivir (Relenza@) are effective against both influenzas A and B by virtue of their antineuraminidase activity. These drugs are competitive inhibitors of influenza's own neuraminidase, an enzyme that cleaves sialic acid residues from the host cell surface. Virions ready for release from an infected cell normally remain attached to the cell's sialic acid residues that are bound to the virion's haemagglutinin protein. Complete release of the virion from the host cell requires neuraminidase to cleave the sialic acid residues. Once released, the new viral copies escape from the infected cell to infect other cells thus propagating the infection. By blocking the active site of the neuraminidase enzyme, the drugs prevent neuraminidase from working so that the spread of the virus is inhibited allowing the host's immune defences to work more quickly and effectively. Tamiflu is taken orally and Relenza by nasal powder spray. Because much of it is destroyed in the stomach and gut a normal dose of Tamiflu contains a greater dose of the active ingredient (Oseltamivir) than the equivalent dose of Relenza 2 which is absorbed without significant breakdown directly in the nasal passage. Possibly because of this Tamiflu is associated with side-effects such as nausea, vomiting and headache which are not a major obstacle to its use or popularity. Of a more serious nature is Tamiflu's link to adolescent deaths nearly all of which have been in Japan. Up to 2006 there have been about 15 deaths, most of them by suicide. Tamiflu is known to be connected with transitory psychiatric disturbance such as sudden aggression, disorientation, delirium, hallucinations, self-injury and suicidal thoughts. - More recently the Japanese ministry of Health Labour and Welfare issued a warning not to prescribe oseltamivir phosphate to adolescents aged 10-19 years following two unusual suicides. However it is not known precisely why Japanese youngsters are so heavily represented. Hoffman LaRoche have recognised this issue and have included appropriate precautions against neuropsychiatric events arising from use of Tamiflu. " Relenza has side effects also but these are mainly a result of the vehicle, lactose that allows it to be sprayed into the nose as a powder. Bronchospasm and respiratory function deterioration are the side effects here neither of which appears to be a major problem in terms of intensity or duration of the effects. Patients with pulmonary problems are advised to seek medical advice before using Relenza. - We believe that the Invention has low risk owing to the known safety of its components. (ii) Development of Drug Resistance - Influenza is a survivor precisely because it is able to mutate, which ability allows it to present a new and previously unseen antigenic makeup to the host. The host must learn this new antigen makeup in order to mount a specific immune response against the new virus. This is why an attack of influenza lasts around 2 weeks, the time for the immune response to develop fully and why vaccines are less effective against a new mutation of influenza. Because of this ability to mutate, influenza can change the nature of its neuraminidase enzyme so that competitive inhibitors such as Oseltamivir and Zanamivir no longer act as inhibitors. Despite its altered nature the new mutated neuraminidase enzyme still cleaves sialic acid residues and helps spread viral particles but is now unaffected by the inhibitors that attempt to block its action. - There are many reports of oseltamivir-resistant strains of influenza A and B emerging while zanamivir resistance does not as yet appear to develop. The author expresses concern that the potential effectiveness of oseltamivir in the case of a pandemic outbreak of influenza will be compromised by the practice of stockpiling the drug. This is thought to lead to inappropriate dosages of the drug in a similar fashion to the way that antibiotic resistance develops i.e. by failure to kill off every organism except the subpopulation that contains the gene for resistance. - Resistance can also arise by virtue of inflammation brought about by a particularly virulent strain of influenza of which the avian strain H5N1 is a prime example. In such cases of inflammation there is widespread attraction of the body's own inflammatory cells including polymorphs and macrophages. These cells release a variety of lytic enzymes into the area of inflammation including proteases that can cleave sialic acid residues in place of the virion's neuraminidase. In such cases, neuraminidase inhibitors have no effect because neuraminidase is irrelevant to the spread of infection. - In the event of a pandemic it is more likely that resistance to Tamiflu and Relenza would develop owing to sudden widespread use. In this event the efficacy of Tamiflu and Relenza could become limited in a short period of time. Those who felt they had taken the correct strategy by stockpiling the drugs would be disappointed to discover that their remedy was a remedy no more. - We believe that the Invention has none of these problems and that resistance to it will not occur. By its nature a herbal remedy is not a pure substance but a spectrum of chemical substances that act in concert by a plurality of synergistic pathways. Almost universally it is found that the unrefined whole plant or crude unseparated extract provides a more effective treatment than any pure, single substance derived therefrom. While the virus might be able to mutate every season into a new strain with a new antigenic form of neuraminidase that is unaffected by drug inhibitors, it is virtually impossible for it to do this against a spectrum of distinct and different antiviral principles found in this herbal remedy. 3 3. Antibiotic medications Antibiotics are effective in treatment of secondary bacterial infections. They are ineffective against viruses of any type. 4. Phytochemicals Previous phytochemical compositions may be effective for prevention and relief of viral infections. In all cases studied they prove inferior to The Invention because: - they are not suitable for children or pregnant women due to known side-effects - they lack broad-spectrum activity against multiple recognized viral activities - there is conflicting evidence - there is difficulty stabilizing and/or delivering the active compounds of the herbal material. These are typical of the examples we have found: - Elderberry has good evidence supporting a patented proprietary product, Sambucol. This product has been shown effective in treatment and relief of Influenza infection, but there is no evidence for a preventive effect. - American Ginseng has good evidence for relief and treatment of colds and flu. However the preventive action is unimpressive, with a relative risk reduction of approximately 10%. - Garlic has conflicting evidence as a preventative or treatment for respiratory infections. The main problem is the volatile nature of the active compounds alliin and allicin, which are difficult to stabilize. Quality of garlic preparations is highly variable and difficult to evaluate. Raw garlic, consumed immediately after crushing, has good traditional evidence but is contraindicated in children younger than five years of age, and in persons suffering gastrointestinal disorders such as peptic ulcer and gastritis. - Echinacea has conflicting evidence, with considerable confusion about the effectiveness of different species, plant parts, dosage and effective components. Extracts are also standardized to a number of different constituents, with variable efficacy. Echinacea may be effective as a preventative of colds and flu but clinical research continues to produce conflicting evidence. - The combination of Eleutherococcus and Andrographis reduces the severity and duration of symptoms but there is no evidence for a preventive effect. - Olive leaf extracts have in vitro and animal, but no human evidence supporting antiviral effects. - Traditional Chinese Medicine herbal formulas are very interesting, but have problems when viewed from a Western scientific perspective. They are normally adjusted by alterations to the formula according to the patient's individual profile, the particular symptoms, the personality of the patient, and the season of the year. While this can be good medical practice, it is difficult to establish efficacy for a particular preparation or herb in such a system. Major problems with Chinese medicines are substitution and contamination; for example the substitution of Aristolochia species for other herbs, which has been responsible for a number of deaths; and the presence of agricultural contaminants such as mercury. Summary of the Invention: The Invention is the synergistic combination of two plants: Ribes nigrum and Glycyrrhiza glabra, with or without other ingredients. The Invention is the combination of Ribes nigrum, containing polyphenols and anthocyanins, and Glycyrrhiza glabra, containing glycyrrhizin and glycyrrhetinic acid; and/or their extracts or derivatives; and/or other herbs with the same or similar components, and/or extracts or derivatives of these; and/or synthetic polyphenols, anthocyanins, glycyrrhizin, and/or glycyrrhetinic acid, and/or derivatives of these; with or without additional ingredients, whether active or excipient; in any quantities, ratios or proportions. 4 The Invention delivers effective, rapid and synergistic antiviral, anti-inflammatory and immunostimulant actions. The synergistic combination of Ribes and Glycyrrhiza blocks every action of the invading virus and protects the body against damage by its own symptoms and by immunological or inflammatory responses. The Invention forms a complete system of protection against influenza, SARS, MERS, Herpes and common cold, and a complete system of treatment for existing infection. The Invention is superior to existing treatments. Due to its low cost, rapid action, synergistic activity, excellent safety profile, and low risk of viral development of resistance, the Invention is an ideal broad-spectrum remedy for influenza, SARS and colds. There is also growing evidence supporting its effectiveness against Hepatitis and HIV. Detailed Description of the Invention The Mechanism of infection Influenza infects and affects humans by several mechanisms. The virus enters the body through the membranes lining the respiratory tract or the alimentary canal, commonly in the nose and throat. It must penetrate the barrier membranes, attach itself to the walls of living cells, and insert its genetic material into the cell. The genetic material penetrates to the interior of the cell nucleus and induces the production of millions of viral copies, which are then released from the cell. The new virus particles then leave the cell, travel through the body and infect other cells. At the same time millions of virus particles are expelled by coughing or sneezing, and are transmitted to other hosts. Similar mechanisms operate with SARS virus and common cold viruses. The initial response of the body to acute viral invasion is swift and aggressive. The immune system recognizes the presence of the viruses, and releases immunoglobulins which attempt to bind to the viruses and disable them. At the same time white blood cells are mobilized which then rapidly multiply and move through the tissues and fluids of the body, attacking viruses with lytic enzymes, generating free radicals with oxidative bursts, and releasing cytokines that trigger the fever response and inflammation. Fever and inflammation are responsible for most of the symptoms of ARVIs, including headaches, muscular pain, congestion and fatigue. Increased secretion of mucus with coughing and sneezing attempt are the body's attempt to expel invaders but of course serve as a vehicle for transmission of the infection to others. The symptomatic stage usually lasts 7-14 days in a healthy human, depending on the viral type. During this time the immune system produces antibodies highly specific to the offending virus, which are produced and released and eventually clear the infection. Specialized lymphocytes memory cells - retain the ability to rapidly release the antibodies specific to that strain of that virus, granting an acquired immunity to the virus which can last for many years. This acquired immunity, of course, is highly specific and gives little protection against new or unknown variants. As ARVIs mutate rapidly, new strains are continually emerging. Thus existing antibodies may become ineffective over time. When a new and virulent viral strain appears in a population with no previous exposure to similar viruses, ie in a naive population, the reaction can be severe. The immune system, unable to mount an immediately effective antibody defense, triggers continued cytokine release, resulting in systemic inflammation: the so-called "cytokine storm" responsible for multiple organ damage and often death. It is important to note that systemic inflammation generates significant oxidative damage to cells and tissues. In this scenario the healthier the person, and the stronger his or her immune function, the more rapid and drastic is the illness. As a result the young and fit may die first, killed by their own immunological and inflammatory responses. If this is coupled with a very contagious virus, an epidemic may result with a high rate of mortality. In the 20th century Spanish Flu, Asian Flu and 5 Hong Kong Flu were responsible for millions of deaths. Spanish flu was responsible for more deaths than World War 1. Influenza constantly mutates by genetic drift and shift into new viral strains; the main source of new variants and epidemics is Southeast Asia and China. The virus is carried by birds in densely populated countries dependent upon poultry for food. Thus there is no practical way to prevent the emergence and spread of new strains. The scenario is similar for SARS and other ARVIs. The Invention prevents against infection by all known and unknown variants of ARVIs; in existing infection it reduces viral replication and transmission; it effectively damps the inflammatory response, thus relieving symptoms while preventing progression of illness to multiple organ failure and death. Glycyrrhiza glabra Licorice root has been traditionally used as an adrenal tonic, an expectorant and as a demulcent in gastric inflammation. It is a component of a large number of herbal formulas. The root contains glycyrrhizin and glycyrrhetinic acid, among other active constituents, which demonstrate a number of relevant properties: - Antiviral, by inhibiting viral adsorption, adhesion and penetration; by inhibiting viral replication, if given in high doses; and by stimulating T-cell release of gamma-interferon. Activity has been shown against EBV, CMV, Hepatitis, Herpes, HIV, Influenza and Coronavirus, among others. - Antiinflammatory: glycyrrhetinic acid inhibits the conversion of the active adrenal hormone cortisol into the inactive cortisone, increasing the half-life and effect of the hormone. Glycyrrhetinic acid and glycyrrhizin also bind to and stimulate glucocorticoid receptors. In addition, several other components of licorice show steroid-like activity. The result is inhibition of the inflammatory mediators Phospholipase A2, Cyclooxygenase (COX) and Platelet Activating Factor (PAF). However unlike cortisol, Licorice does not suppress immune function. - Mucoprotective: Licorice increases mucus production by mucous membranes throughout the body, contributing to the physical barrier of the membranes against viral entry. - Immune stimulant: Licorice raises the count of T-cells and increases the production of interferon. - Antioxidant: Licorice inhibits the generation of free radicals by neutrophils, and contains a number of antioxidant constituents. Licorice has been used as a sweetener and as a medicine for thousands of years. Low doses (up to 5g per day) are suitable for long-term use. 3g per day is suitable for pregnant women. Higher doses (5-15g per day) can be taken for 4-6 weeks without supervision. Ribes nigrum Blackcurrants are very rich in the blue and purple polyphenolic pigments of the anthocyanin family, whose members include anthocyanins, proanthocyanins, oligomeric proanthocyanins (OPCs or PCOs) and their derivatives. These pigments are present in a large number of plants, and perform several protective functions. They are powerful antioxidants, and help to protect the plant against ultraviolet light. They have antiviral, antibacterial and antifungal activity, helping to protect the plant against infection. In some cases they are toxic to insects. When these compounds are taken by humans, they confer their protective functions on the consumer. - Antiviral, by strengthening the connective tissues against viral entry; by inhibiting viral attachment to cell membranes; by preventing viral replication inside cells; and by preventing viral release from infected cells. Activity has been shown against Influenza, Coronavirus, HIV and Herpes infections. - Immune-stimulating, by regulating cytokine release. - Anti-inflammatory, by regulating cyclooxygenase and lipoxygenase enzyme systems and 6 so controlling the synthesis and release of prostaglandins, leukotrienes and related inflammatory mediators; and by inhibiting the degranulation of mast cells, thus preventing the release of histamines. In combination, this down-regulates the inflammatory response. - Antioxidant and free-radical scavenger, around 50 times as powerful as vitamin C or E. The antioxidant activity is important in protecting the tissues against oxidative damage produced in the inflammatory process - Connective tissue strengthening, by cross-linking and stabilizing the fibres of collagen; by stimulating the synthesis of mucopolysaccharides in the ground substance of the mucosal membranes; and by inhibiting inflammatory enzymatic cleavage. This maintains the integrity of barrier membranes of the skin, airways and gut against both microbial entry and inflammatory damage. When these compounds are taken by humans, they confer their protective functions on the consumer. - Antiviral, by strengthening the connective tissues against viral entry; by inhibiting viral attachment to cell membranes; by preventing viral replication inside cells; and by preventing viral release from infected cells. Activity has been shown against Influenza, Coronavirus, HIV and Herpes infections. - Immune-stimulating, by regulating cytokine release. - Anti-inflammatory, by regulating cyclooxygenase and lipoxygenase enzyme systems and so controlling the synthesis and release of prostaglandins, leukotrienes and related inflammatory mediators; and by inhibiting the degranulation of mast cells, thus preventing the release of histamines. In combination, this down-regulates the inflammatory response. - Antioxidant and free-radical scavenger, around 50 times as powerful as vitamin C or E. The antioxidant activity is important in protecting the tissues against oxidative damage produced in the inflammatory process - Connective tissue strengthening, by cross-linking and stabilizing the fibres of collagen; by stimulating the synthesis of mucopolysaccharides in the ground substance of the mucosal membranes; and by inhibiting inflammatory enzymatic cleavage. This maintains the integrity of barrier membranes of the skin, airways and gut against both microbial entry and inflammatory damage. Black Currant fruit and its juice, as well as various preparations such as jellies and robs, have been traditionally used to relieve respiratory infections. The dose prescribed in the traditional literature is to take the juice or preserve, diluted in hot water, several times at the onset of a cold or flu. The quantity of fruit is unclear but was very likely in the range of 20-50g per day, often taken as dried berries made into a tea. Its safety is demonstrated by the fact that the berries have been freely used as both food and medicine for thousands of years. There are no recorded adverse effects or interactions. Synergy Definition: synergy is the interaction of two or more treatments such that their combined effect is greater than the sum of the individual effects observed when each treatment is administered alone. A good example is the combination of pyrethrum with piperonyl butoxide in household insecticides. Pyrethrum is an effective insecticide. Piperonyl butoxide, not itself an insecticide, disables the enzyme system which breaks down pyrethrum, thus removing the insect's defence and increasing the toxicity of the pyrethrum. Internal synergy: In plant and animal tissues, internal synergy is well recognized, for example in the antioxidant systems. Free radicals generated by ionizing radiation, metallic ions or energy metabolism, for example, can indiscriminately damage structures in both the aqueous and lipid compartment of 7 the body. Thus a water-soluble antioxidant such as vitamin C will protect only aqueous compartments, while a lipid antioxidant such as vitamin E will protect only lipid compartments. When the ability of vitamins C and E to regenerate each other is added, this means that the combination of the two gives superior protection. In the living human body, as in plant tissues, there is a wide range of antioxidants working in concert, including vitamins, carotenoids, flavonoids, OPCs and free-radical scavenger enzymes. Using the example of the antimalarial herb Artemisia annua, the main active principle artemisinin is potentiated in the presence of the methoxylated flavones in the plant. Thus the crude extract is more effective than the purified chemical entity. In the present Invention, both blackcurrant and licorice owe their effectiveness to a number of internally synergistic components. Herbal medicine takes deliberate advantage of this internal synergy in plants. This is the reason for the use of plant extracts which resemble the chemical makeup of the plant material as closely as possible. External synergy: Herbal medicine regularly employs external synergy in the skilful combination of plant medicines. For example, in the treatment of gastric ulcer, a combination of the herbs golden seal, calendula and slippery elm is highly effective. The golden seal is antibacterial and effective against Helicobacter pylori, removing the immediate cause of the ulcer; the calendula stimulates repair of the gastric lining; and the slippery elm produces a mucilaginous coating which covers the ulcerated surface, preventing contact with gastric acid and pepsins, thus preventing further chemical damage to the tissues. The combined effect is rapid relief of pain, despite the fact that none of these remedies has any direct pain-relieving effect. In the present Invention, Ribes and Glycyrrhiza have been combined in order to produce broad spectrum and multilayered antiviral activity, both against the whole spectrum of viral mechanisms of entry, replication and transmission; and against the widest possible range of infectious viruses. Although the sum total of the actions of the invention are not synergistic in the Western Sense, they are synergistic within the meaning of synergy as used in Traditional Chinese Medicine. The mechanism of the Invention: to block viral entry, activity and damage. 1. The Invention prevents infection with influenza, SARS and common cold via inhibitory actions operating at recognized stages of viral infection and replication. a) The virus is inhaled or ingested and reaches the mucus barrier of the respiratory or gastrointestinal tract. " Glycyrrhiza stimulates the cells of the mucous membranes to increase the thickness of the mucus barrier. " This inhibits viral adhesion to the cell membranes. b) The virus penetrates the mucus barrier to reach the lining membranes. - Ribes strengthens the connective tissue of the membranes by cross-linking collagen fibres and stimulating the production of mucopolysaccharides in the ground substance. " This inhibits viral access to the cell membranes. c) Hemagglutinin antigen on the viral surface binds to sialic acid residues on the cell membrane. Viral neuraminidase antigen cleaves the sialic acid residues and allows the virus to enter the cell. - Ribes inhibits hemagglutinin. - This prevents viral attachment to the cells and subsequent entry to the interior of the cell. d) The virus penetrates the cell membrane and enters the cell. Here it induces replication and production of new daughter virus particles. - Glycyrrhiza and Ribes both inhibit viral replication within the cell. e) Viral haemagglutinin antigen on the daughter virus particles binds to sialic acid residues on the cell membrane; neuraminidase cleaves these and allows the daughter viruses to exit the cell, transmitting infection to other tissues and hosts. Ribes inhibits neuraminidase. 8 - This prevents spread of the infection to other cells and tissues. - By comparison this is the only mechanism by which Tamiflu and Relenza work. 2. The Invention reduces the risk of systemic inflammation, consequent organ damage and death, via the following mechanisms: a) The presence of the virus in the bloodstream triggers the white blood cells to release inflammatory mediators including prostaglandins, leukotrienes and cytokines. - Flavonoids in Ribes inhibit both cyclo-oxygenase and lipoxygenase enzymes, limiting the release of prostaglandins and leukotrienes, and thus damping the inflammatory response. - Glycyrrhiza reduces inflammation by stimulating cortisol receptors to inhibit the activity of inflammatory enzymes including phospholipase A2, cyclo-oxygenase and platelet activating factor. b) Inflammatory mediators trigger the release of enzymes that break down connective tissue barriers. - Flavonoids in Ribes inhibit enzymatic cleavage of connective tissues. c) Inflammation triggers free radical production with consequent oxidative damage to cells and tissues. - Flavonoids in Ribes are potent antioxidants and free radical scavengers and reduce oxidative damage. " Glycyrrhiza contains a number of antioxidant constituents. d) Uncontrolled inflammation in a naive or susceptible individual (the cytokine storm) may lead to organ damage, organ failure and death. Because inflammation is reduced by Ribes and Glycyrrhiza the cytokine storm is less likely to develop or progress. 3. The Invention rapidly relieves the signs and symptoms of acute respiratory viral infections, via the following mechanisms: a) Symptoms of acute viral infection are a direct result of the release of inflammatory mediators. - Flavonoids in Ribes inhibit both cyclo-oxygenase and lipoxygenase enzymes, limiting the release of prostaglandins and leukotrienes, and thus the inflammatory response. - Glycyrrhiza reduces inflammation by stimulating cortisol receptors to inhibit the activity of inflammatory enzymes including phospholipase A2, cyclo-oxygenase and platelet activating factor. 4. The Invention decreases the number of sick days and reduce time to full recovery via the following mechanisms: a) Once inside the cell, the virus replicates rapidly, producing millions of viral copies per day, which spread rapidly to other cells and tissues, increasing the viral load exponentially and triggering ongoing inflammation, immune activation and fever. These are the direct causes of the symptoms of infection. - Glycyrrhiza and Ribes inhibit viral entry and replication, and damp inflammation, as described above. - Reduction of viral replication, viral load and antigenic stimulus reduces the severity and duration of the immune response, fever and inflammation, and therefore their direct consequences, the symptoms of illness. 5. The Invention inhibits transmission of acute respiratory viral infection via the following mechanisms: a) Once inside the cell the virus induces replication and production of daughter virus particles. - Glycyrrhiza and Ribes both inhibit viral replication within the cell. b) The daughter viruses exit the cell and invade other cells, tissues and humans. - Ribes inhibits neuraminidase and prevents release of the viral particles, preventing them from spreading to infect other cells, tissues or humans. 9 6. The Invention has broad-spectrum activity, ie it is highly effective against a wide range of influenza viruses including Influenzas A, B, C and avian influenza by the following mechanisms: a) All acute respiratory viral infections must penetrate the cell to replicate. They must penetrate the mucus barrier of the mucous membranes; penetrate the lining membranes; bind to cell receptor proteins; and replicate inside the cell. " Glycyrrhiza stimulates the cells of the mucous membranes to increase the thickness of the mucus barrier. This inhibits viral adhesion to the cell membranes. - Ribes strengthens the connective tissue of the membranes by cross-linking collagen fibres and stimulating the production of mucopolysaccharides in the ground substance. " This inhibits viral access to the cell membranes. - Ribes inhibits viral attachment to the cells and subsequent entry to the interior of the cell. - Glycyrrhiza and Ribes both inhibit viral replication within the cell. 7. Unlike synthetic anti-influenza medicines, such as Oseltamivir and Zanamivir, resistance to the Invention will not develop for the following reasons: a) Oseltamivir and Zanamivir employ a single mechanism for preventing infection: they inhibit viral attachment by blocking neuraminidase activity. Sooner or later mutation will give rise to a variant which is less dependent on this mechanism, and thus unaffected by the drugs. - The Invention employs at least five distinct mechanisms to prevent viral entry and replication. Variants may evade one or more mechanisms but are unlikely to develop resistance to five. - Plants have been resisting viral attack for millions of years longer than animals, including humans. They typically employ multiple antiviral mechanisms. Use of these plants in the form of herbal extracts takes advantage of their complex systems of defense. 8. The Invention is free from serious side-effects and can in normal conditions be tolerated by the population at large: children, pregnant mothers, the frail, the elderly and those with pre-existing conditions such as bronchial impairment. a) The Invention is composed of herbal compounds, each with a history of safe usage over centuries. b) Glycyrrhiza has been used for many hundreds of years as a medicine in pregnant women, children, the elderly and the sick. Side effects are mild and occur only with long-term use of high doses. - In high doses Glycyrrhiza has a weak aldosterone-like action, causing sodium retention and potassium loss. These over time can raise blood pressure and produce palpitations. " The Invention may for the same reason cause interactions with diuretic or antihypertensive prescription medications. - To counteract this the preferred embodiment of The Invention will contain potassium, and will carry a warning that persons using such medications consult their health provider before using the product. c) Ribes has been used both as a food and as a medicine for hundreds of years in high doses, with no recorded adverse effects. 9. The Invention employs a synergistic approach in order to prevent and treat acute viral infection, in which each layer of defence supports every other layer. The immune system employs multiple layers of defences, all with attendant costs in energy and biochemical work. The invention produces an effective and energy-efficient reinforcement at every stage of this system of defence. 10 Preferred embodiment of the Invention: The antiviral effects of the Invention are to be tested on influenza, rhinoviruses, coronaviruses, cytomegalovirus, herpes and hepatitis viruses. Thus the preferred aspects of the Invention are these viruses, but without limitation to other infectious organisms as yet un-tested. The formulation of the Invention may be effective below the thresholds specified, and has limited risk above the thresholds, but in a preferred embodiment the amount of the compounds will be between: - Ribes nigrum 0.5g to 50g equivalent - Glycyrrhiza glabra 0.5g to 15gequivalent With or without the addition of: - Potassium 50-250mg to replace potassium loss potentially caused by high doses of Glycyrrhiza - Piperine 1-10mg to increase the gastrointestinal absorption of the herbal preparations with or without other ingredients, in doses and forms as determined to be suitable; and this to be a single dose. In a preferred embodiment two doses per day would protect an adult person of 50-80 kg body mass. A child would take one dose per day. A large person, a person exposed to exceptional exposure risk, or a person with stomach upset, may take one dose twice daily. In a preferred embodiment 2-6 doses may be taken per day for rapid treatment of existing infection. In a preferred embodiment the Invention is prepared as a powder in a sachet, as a capsule, or as a tablet which is scored and / or waisted to allow it to be easily and cleanly broken in two, for ease in swallowing and / or for administration to a child. The Invention may be made available in any or all of these forms, or other forms as developed from time to time. a) Tablet b) Capsule c) Syrup d) Liquid e) Powder f) Flavoured powder g) Sachet h) Nasal delivery, for example with a spray i) Aerosol delivery, for example with puffer or spacer j) Transdermal application, for example with a patch, cream or gel k) Suppository I) Sterile intravenous or intramuscular injection m) Sterile injection by low pressure injector The Invention may be made available for any or all of: a) Humans. b) Domestic animals including but not limited to cagebirds, cats and dogs. c) Commercial animals including but not limited to poultry and swine. d) Sporting animals including but not limited to horses. 12

Claims

1. Is the synergistic combination of any preparations of the two herbs Glycyrrhiza and Ribes, or any other berry fruit or source of anthocyanins, with or without the addition of other ingredients, in a range of proportions between 1:100 and 100:1 and given as a dose from a minimum of 100mg per person per day over a period of a minimum of 3 days (for treatment) or 7 days (for prevention).

2. In the formulation range as described above, and taken as treatment over the range above, provides a therapeutic effect, that is protection against and / or treatment and relief of influenza and other viral infections.

3. Provides synergistic protection against, as well as treatment and relief of, influenza and other viral infections. Synergistic protection is here defined as the ability of the said combination of herbs, herein described, to provide a significantly greater therapeutic effect than either herb taken alone.

4. Is effective in the prevention of all forms of influenza and acute respiratory viral illness

5. Prevents infection with influenza virus in up to 90% of humans.

6. Has broad-spectrum activity, ie it will be highly effective against a wide range of viruses including Influenzas A, B, C ; avian influenza; SARS; common cold; herpes; and others.

7. Is effective in the treatment of all forms of influenza and acute respiratory viral illness

8. Rapidly relieves the signs and symptoms of existing influenza infection.

9. Decreases the number of sick days and reduces time to full recovery.

10. Enhances immune function

11. Inhibits viral transmission

12. Inhibits the inflammatory cytokine storm, systemic inflammation, consequent organ damage, and reduces the risk of death.

13. Is free from serious side-effects and under normal conditions can be tolerated by the population at large: children, pregnant mothers, the frail, the elderly and those with pre existing conditions such as bronchial impairment.

14. Unlike synthetic anti-influenza medicines, such as Oseltamivir and Zanamivir, will not be affected by development of resistance in viruses. 12