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Phytotherapy in an influenza pandemic.

Swine flu

The risk of a global influenza pandemic has surfaced again in recent months, following outbreaks of a new form of influenza A (H1N1) causing illness in humans, commonly known as 'swine flu'. First detected in Mexico and the United States in March and April 2009, the appearance of this virus and its association with a high rate of human to human transmission is leading to increasing concerns that a pandemic is imminent.

This new virus was originally called swine flu because laboratory testing showed that many of its genes were very similar to influenza viruses that normally occur in pigs in North America. Actual swine flu is a highly contagious acute respiratory disease of pigs caused by one of several swine influenza viruses. The H1N1 subtype of influenza A virus is the most common, but other subtypes also circulate in pigs (eg H1N2, H3N1, H3N2).

However this virus is different from that normally circulating in North American pigs in that it has two genes from influenza viruses that usually circulate in pigs in Europe and Asia as well as avian genes and human genes. This novel reassortment of H1N1 from avian, swine and human strains, has resulted in a virus which appears to be significantly more infectious than ordinary seasonal influenza.

A similar dual infection of avian influenza and human influenza viruses in pigs is thought to have led to genetic reassortment and development of human forms of the 1957 and 1968 pandemic strains of influenza A.

Transmission appears to occur by the same routes as other influenza viruses, through person to person spread via coughing (large particle respiratory droplets), although contact with droplet contaminated surfaces is another possible route. Little information on transmission of the virus is available as yet, but other non respiratory bodily fluids of swine influenza cases may also be potentially infectious.

Symptoms are typical of influenza and include fever, headache, upper respiratory tract symptoms (cough, sore throat, rhinorrhea), myalgia, chills and fatigue. Diarrhea and vomiting can also occur and as with seasonal flu, severe illness and death can occur.

Pandemic risk

At the time of writing, human swine flu is spreading rapidly around the world. By 5 June this year, 69 countries had officially reported 21 940 cases of infection with this virus, and there had been 125 deaths (www.who.int/ feeds/entity/csr/disease/swineflu/en/rss.xml).

The number of cases is rising rapidly having reached 15 000 just a week earlier on 31 May. Australia confirmed its first case on 9 May, a women arriving on a flight from Los Angeles to Brisbane. By 1 June this had risen to 297 cases, and by 6 June to 1009 cases, at which time suspected cases were no longer being reported by the Department of Health and Ageing because these were changing too quickly to report.

The rapid spread of this H1N1 virus around the world within a very short timeframe has highlighted the vulnerability of human populations to influenza viruses, and the ease with which these can spread through overseas travel by modern populations.

The early outbreaks in Mexico were associated with a large number of cases of fever and severe respiratory illness and an alarmingly high frequency of death. Most of these were aged 5 to 59 years, with females being somewhat more affected than males.

As at 1 June, 5029 cases had been reported in Mexico (97 deaths), 8975 in the US (15 deaths) and 1336 in Canada (2 deaths).

Despite its rapid spread the effects of the virus to date appear to have been less virulent in other countries it has spread to. Most people who have become ill have recovered without requiring medical treatment, and the symptoms experienced have been typical of those seen with seasonal flu.

This mildness of symptoms and low death rate experienced among H1N1 patients to date outside of Mexico, has lead to scepticism and dismissiveness by many about the scale of media coverage and warnings from public health officials. The failure of the so called 'bird flu' H5N1 pandemic to emerge despite similar concerns and warnings a few years ago (Rasmussen 2005a, 2005b) has also fed such cynicism and allegations of the current situation being 'a storm in a teacup'.

Nevertheless as at early June the pandemic alert in the World Health Organisation (WHO) Global Influenza Preparedness Plan is at phase 5, only one phase short of a global pandemic. This is characterised by human to human spread of the virus into several countries in one region and is a strong signal that a pandemic is probably imminent.

A pandemic is defined as a worldwide epidemic involving a new virus to which populations have no or little immunity. This WHO alert, and the numerous statements about the inevitability of swine flu becoming a pandemic being made by infectious disease experts in many countries at present, give a consistent message.

Health authorities around the world including Australia, are taking this new virus seriously and are on a high level of alert. Schools and creches have been closed, travellers screened for flu symptoms, and those identified as being infected with influenza A or having travelled from or been exposed to someone recently arrived from an affected region of the world, have been quarantined. Those with symptoms suggesting influenza infection have also been quarantined when arriving from a high risk area such as the United States or Mexico. In virtually all cases these individuals have been treated with the antiviral drug Tamiflu[R] as a precautionary measure.

Reasons for such a heavy handed approach by authorities seem justified. The 1918-1920 influenza pandemic, also caused by an H1N1 strain, infected at least one third of the world's population at the time and killed more than 50 million people worldwide including 8500 New Zealanders and 12 000 Australians. While this originally began in a mild form, arriving in Australia and New Zealand in November 1918, it returned as a second wave in the autumn in a far more lethal form (Potter 2001, Crosby 1976, Reid 1999) then again in the winter. In each of the three waves infection rates and the pattern of spread varied, but an unusual feature was that it killed mostly young adults rather than predominantly the very young and very old.

Such a wave like pattern has been a feature of pandemics within the last century and for many reasons the severity of subsequent waves can differ dramatically in different countries. The relatively high death rates from avian H5N1 in Indonesia, Vietnam and Egypt a few years ago, and H1N1 recently in Mexico, probably has some relationship to population density as well as public health and animal farming systems in these countries.

The current H1N1 virus appears to be much less pathogenic in most populations than early outbreaks in Mexico indicated, but influenza viruses mutate and continue to evolve generally at a rapid rate. The rapidity of spread of this virus throughout many countries, and its entry to Australia at the start of the winter influenza season, are reasons for concern. Winter creates more suitable conditions for the spread of flu and if there is widespread circulation of H1N1 as seems to be occurring, its exposure to other influenza viruses and therefore potential to exchange genetic material with these and mutate, is inevitably increased.

While mutations could be to either a more benign or more dangerous form, there is little that human intervention can do to steer this process, and an analysis of historical patterns suggests the next major influenza pandemic is well overdue (Potter 2001).

In most countries mainstream healthcare services are already under some pressure due to aging populations and increased service demand over recent years, combined with cost increases, budgetary constraints and staff shortfalls in many sectors. Seasonal influenza alone kills 250 000 to 500 000 people each year and can place enormous strains on hospital and community healthcare services, even in wealthier countries. While public health measures to manage such a pandemic are well developed in many countries, others seem poorly prepared.

Should a human outbreak of a new highly pathogenic strain of the current swine flu or another influenza virus occur, the sudden surge in demand for finite health services resources, combined with what will almost certainly be limited supplies of efficacious antiviral drugs, and the absence of a suitable vaccine, will cause conventional health services to become rapidly over burdened. These sobering facts point strongly to the likelihood that other self help measures including herbal treatment or prophylaxis will thus take on a greater role.

It is therefore necessary for phytotherapists and other clinicians to have some knowledge of this subject and to appraise the evidence of possible usefulness of various herbal medicines should such a situation emerge in the near future.

Conventional treatment

Neither natural immunity from earlier strains of influenza A nor currently available vaccines offer protection against the current form of swine flu. While this winter has seen an even stronger campaign than usual to encourage populations to receive the seasonal flu vaccine, with the suggestion that this may reduce the exposure of swine flu to other influenza A genes and thus its ability to mutate, this is highly conjectural.

To date suspected, probable and confirmed cases have been treated with the neuraminidase inhibitor drugs oseltamivir (Tamiflu[R]) and zanamivir (Relenza(r)). These drugs inhibit neuraminidase, an essential viral glycoprotein for virus replication and release, and thus block the release of the influenza virus from infected cells and inhibit its transmission to neighbouring cells. Tamiflu[R] (oral) and Relenza[R] (oral inhalation) are currently the only available drugs likely to help contain an influenza A virus and reduce illness and death (Leneva 2000, Govorkova 2001).

However these drugs need to reach the site/s of any pandemic outbreak quickly and be taken early following infection to be effective. While Australia appears to have a stockpile of 8.7 million doses of Tamiflu[R] and Relenza[R], the situation in most other countries is considerably less reassuring. Global stocks of these drugs are currently estimated to be sufficient to treat only about 5% of the world's population, and less if used propylactically.

While manufacturing capacity can expand following the onset of a pandemic to an output of sufficient drug to treat 400 million people, this is still only a fraction of possible global demand (Coker 2009). Poorer countries in particular do not have such stocks, or the public health resources in existence in wealthier countries.

Additionally it is intrinsic to the nature of infectious microorganisms that they have an incredible capacity to develop resistance to commonly used antiviral and antibacterial drugs, and the likelihood of this is increased the more they are exposed to the drug/s concerned. With use of oseltamivir for seasonal influenza being common in Japan for many years and on the increase in other countries including New Zealand and Australia since 2006, it is no surprise that cases of resistance to it are increasing (Le 2005, McKimm-Breschkin 2005). While both oseltamivir and zanamivir seem to have some efficacy against the current form of swine flu, it is unknown whether this will extend to future variants.

Like H5N1 avian influenza, the recent H1N1 swine influenza virus isolated from humans is resistant to the antiviral drugs amantadine and rimantadine.

During the H5N1 influenza scare some years ago it became apparent that global vaccine production capacity was insufficient to meet world demand during an influenza pandemic. A British virologist stated recently that initial H1N1 vaccine development would only cover about 15% of the UK population (Oxford 2009). Companies that produce vaccines are also now faced with a dilemma over whether they should produce vaccines for seasonal influenza, swine flu or both.

While vaccine development has recently begun and the Australian government has apparently ordered 10 million doses, supplies are unlikely to be available until August. As the virus could mutate significantly during the southern hemisphere winter, this initial vaccine could also be useless by the time seasonal flu returns to the northern hemisphere later this year.

Influenza virulence and immune response

Like other influenza viruses, the H1N1 swine flu virus seems to enter the body through mucous membranes in the throat, nose or eyes, then takes up residence in the respiratory tract and begins to replicate. In general it does not seem to move outside of the respiratory tract although the high frequency of diarrhea and detection of viral RNA in faecal samples, suggests gastrointestinal tract involvement.

While little is known as yet about the current H1N1 virus, investigations into the molecular mechanisms underlying the pathogenesis and strongly virulent nature of H5N1 infections during the recent avian influenza scare have produced some interesting findings.

Evidence from these studies suggests that the severity of H5N1 influenza virus induced disease in humans seems to correlate with the ability of virulent strains to induce proinflammatory cytokines in macrophages (Guan 2004, Cheung 2002). Acute infection with a highly virulent H5N1 strain seems to produce an excessive immune response of cytokines including induction of high levels of tumor necrosis factor alpha (TNF[alpha]) and other pro-inflammatory cytokines such as macrophage inflammatory proteins, interleukins 1[beta], 6, 12 and 18, and granulocyte colony stimulating factor in monocyte derived macrophages (Guan 2004, Cheung 2002, Kobasa 2004). The virus also seems to have a mechanism that dampens other immune responses such as decreasing levels of the anti-inflammatory cytokine IL-10.

This results in a type of inflammatory cascade known sometimes as a cytokine storm or cytokine dysregulation whereby the release of inflammatory cytokines in response to an infective microorganism is unrestrained by normal feedback mechanisms. Upregulation of genes involved in apoptosis, tissue injury and oxidative damage are additional potentially damaging effects observed for recombinant virulent H5N1 viruses (Kash 2004).

The combined effect of these processes is the promotion of granulocyte infiltration into the lungs resulting in acute lung injury and an unusually severe disease. Animal studies as well as the clinical presentation of severe lung symptoms progressing to multiorgan failure often seen during acute H5N1 infection in human victims (Guan 2004, Kobasa 2004, Lipatov 2005, Lee 2005) support this. A shutdown of several different organs in the body, in conjunction with respiratory distress, can result in rapid death (Lipatov 2005). Avian influenza has killed 262 of the 433 laboratory confirmed cases as at 2 June making it much more virulent than other influenza viruses to date.

Studies into a resurrected version of the 1918 pandemic H1N1 virus taken from frozen victims, as well as documented descriptions of symptoms and their severity, suggest a similar course of illness and development of multiple organ failure probably took place. Such immune dysregulation following viral infection of the respiratory tract is known to occur for other highly pathogenic viruses (Gray 2005, Wang 2005). The virulence of SARS, a coronavirus associated severe acute respiratory syndrome which caused 774 deaths in 2003, was also associated with persistence of lung inflammation and high levels of lung cytokines due to delayed clearance of the aetiological coronavirus (Wang 2005).

As mentioned above, while little is known as yet about the H1N1 swine flu virus and how it affects humans, variants to date appear to produce a similar symptom picture to that seen in seasonal influenza, in most cases. However a feature of influenza pandemics where virulence has been particularly severe, including the H5N1 avian influenza and the 1918 H1N1 influenza, seems to be that those with relatively robust immune systems were primarily affected.

Natural treatment approaches Preventing Infectivity

Public health and basic hygiene measures such as covering the nose and mouth when coughing or sneezing, frequently washing hands with soap and water, and staying away from others when ill, all have the potential to help prevent the spread of the H1N1 virus. Wearing face masks, while psychologically appealing, probably has little impact in preventing airborne spread of the influenza virus although the use of respirators seems to have some value.

Another possible mode of preventing infection involves inhibition of adsorption of virus particles at the viral entry route to the target cell surface in the bronchial epithelium. Many plant polyphenolic compounds have exhibited in vitro antiviral activities probably due to non specific binding to and agglutination of viral proteins such as hemagglutinin or neuraminidase. If administered in a timely manner to the site of infection in the respiratory tract a localised antiviral activity could be useful. Examples of such compounds include tannic acid, epigallocatechin gallate, theaflavin digallate and green tea catechins, all of which can inhibit influenza virus replication in vitro. Antiviral properties reported for tannin rich plants Castanea (chestnut) and Schinopsis (quebracho) species, Potentilla tormentilla and Geranium sanguineum probably relate to a similar mechanism (Serkedjieva 2008, Tomczyk 2009, Lupini 2009).

A polyphenol rich extract of the Mediterranean plant Cistus incanus (pink rockrose) has shown potent antiinfluenza virus activity against highly pathogenic forms of H7N7 and H1N1 influenza A viruses both in vitro as well as in a mouse infection model (Droebner 2007, Ehrhardt 2007). Treatment involved local application as an aerosol formulation similar to that of Relenza[R].

Intranasal application of a polyphenol rich extract from Geranium sanguineum has shown a similar protective effect against H3N2 and increased peritoneal and alveolar macrophage numbers in infected as well as healthy mice (Serkedjieva 2008). This restoration of suppressed phagocyte function in influenza A virus infected mice was linked with increased survival time, reductions in both the mortality rate and infectious virus titre, and less deterioration in lung function.

Enhancing resistance

Many unanswered questions remain in terms of how to optimise an efficacious immune response yet spare the host from excessive inflammatory damage to the respiratory tract during infections with highly virulent influenza strains. As with all infectious diseases however, the level of pre-existing immunity to the microbial pathogen is a key factor known to influence the severity of an influenza pandemic or epidemic. Serum antibodies to the viral hemagluttinin glycoproteins (Potter 1979) induced by prior infection or vaccination are the best form of resistance and impart a strong and disease specific host resistance to the virus.

However with the likelihood of an effective vaccine against a pandemic strain becoming available in time being remote, other possible methods of enhancing the immune system's ability to either ward off or successfully resist influenza infection should be considered.

Echinacea species

Echinacea has been shown in animal studies to impart protection against mortality from various viruses (Hayashi 2001, Currier 2001) and several clinical trials have shown beneficial effects of Echinacea during the treatment of colds and influenza (Giles 2000, Melchart 2000, Percival 2000, Hoheisel 1997, Barnes 2005). A meta-analysis of 14 different Echinacea clinical trials published in 2007 concluded it was useful in both reducing the incidence of and duration of the common cold (Shah 2007).

Increased numbers of circulating white blood cells, monocytes, neutrophils and natural killer (NK) cells, and the phagocytotic abilities of these, are the principle immunological changes associated with Echinacea root usage. These effects are all a reflection of enhancement of the non specific immune response whereby the body's ability to maintain immunosurveillance against a variety of potential viral or bacterial pathogens or spontaneous developing tumours is increased.

At first glance certain of the above effects of Echinacea may seem counterproductive during the acute stage of an established serious influenza virus infection in which much of the immune system could in fact be 'over activated'. While activation of innate immune mechanisms such as NK cell activity is useful in the early immune response to most types of influenza (He 2004, Liu 2004), excessive enhancement of NK cell activity during the acute stage of an H5N1 infection for example, could be associated with a theoretical worsening of lung function (Wei 2005).

However recent research as well as traditional usage information suggests that Echinacea root exhibits pharmacological actions better summarised as being immunomodulatory and anti-inflammatory rather than simply immunostimulant. Anti-inflammatory effects of Echinacea root are well established from both its traditional use as well as modern pharmacological studies (Tragni 1988, Muller-Jakic 1994, Clifford 2002, Rasmussen 2002, Zhai 2009).

Echinacea alkamides also produce a dual modulatory rather than simple stimulant effect on TNF-[alpha] expression in humans (Gertsch 2004).

These and other effects of Echinacea on gene expressions indicate a broad spectrum anti-inflammatory and immunomodulatory response (Randolph 2003) including reduced expression of IL-1[beta], IL-8 and TNF-[alpha]. Reversal of the induction of multiple pro-inflammatory cytokines associated with upper respiratory tract rhinoviruses and influenza has also been reported during Echinacea use (Sharma 2009).

Such effects could well contribute to the many benefits of Echinacea and be helpful during the acute stages of highly virulent and perhaps other less virulent forms of influenza virus infection. In addition to these anti-inflammatory and immunomodulatory effects, antioxidant actions by Echinacea could be helpful during this situation (Goel 2005). While adequate doses of a good quality Echinacea preparation have been shown to enhance the immune system's ability to combat existing upper respiratory tract infections, whether such effects would occur to help hasten elimination of a highly virulent influenza infection remains unknown.

The question arises as to whether Echinacea is best used as a possible preventative agent to optimise immune defences ready for when an influenza pandemic occurs or as a treatment when an individual infection has occurred. Based on current evidence Echinacea imparted optimisation of immunosurveillance and the activity of the non specific immune system against a variety of pathogens, while perhaps less likely to ensure complete protection than appropriate vaccination, would seem a promising step to help prevent the onset of infection.

Other phytomedicines

American ginseng (Panax quinqefolium) root has a protective effect against winter influenza in institutionalised older adults (Rasmussen 2004). More recently a preventative effect against winter colds has been reported following daily use for 4 months in a Canadian study involving 323 subjects aged 18-65 years (Predy 2005). A higher immune response from influenza vaccination has also been produced by concurrent administration of the closely related Korean ginseng (Panax ginseng) (Scaglione 1996).

Andrographis (Andrographis paniculata)

A combination preparation of Andrographis and Eleutherococcus senticosus has shown efficacy in both adults and children with early noncomplicated upper respiratory viral infection (Melchior 2000, Shakhova 2003, Poolsup 2004). Quicker recovery and a lower risk of post influenza complications has been reported in a Russian trial comparing this product with the antiviral drug amantadine (Kulichenko 2003).

Baptisia tinctoria and Thuja occidentalis

A combination of Thuja occidentalis, Baptisia tinctoria and Echinacea root has shown efficacy against influenza A infection in mice when administered 6 days before exposure (Bodinet 2002). This formulation has also been reported to reduce the intensity and duration of acute cold symptoms in adults (Henneicke-von 1999).

Umckaloabo (Pelargonium sidoides)

The tuber of this native South African plant has shown positive results in clinical trials involving patients with acute bronchitis (Matthys 2003, Agbabiaka 2008) as well as reducing the severity of symptoms and shortening the duration of the common cold (Lizobug 2007).

The popular Chinese herb Astragalus membranaceous, traditionally used to help manage viral infections such as the common cold, has shown some evidence of immune stimulation and antiviral effects (Block 2003, Yesilada 2005, Guo 2004).

Elderflower (Sambucus nigra) is generally used for its diaphoretic and decongestant properties, particularly during conditons associated with the common cold or influenza. The popularity of elderberry as a remedy for influenza has risen during recent years following favourable results from two clinical trials which found large doses to have in vitro antiviral and immunomodulatory effects and to reduce the duration and severity of influenza symptoms (Zakay 1995, 2004). An appraisal of the traditional uses of various other berries suggests that a number of others probably possess similar properties. These include several Juniperus, Cupressus, Vaccinium and Lonicera species which possess useful antioxidant and anti-inflammatory properties due to their rich content of anthocyanins, flavonoids and essential oils, and contain antiviral constituents (Lipson 2007, Yu 2008, Loizzo 2008, Tang 2009).

The long history of use and folklore popularity of garlic (Allium sativum) as a useful agent in the treatment of various infectious diseases including viruses, and general accessibility of most populations to this herb, warrant further investigations.

The root of ginger (Zingiber officinale), another widely available herbal remedy, has immunomodulatory (Sohni 1996) and antiviral properties (Denyer 1994, Dugenci 2003, Chrubasik 2005) which along with its anti-inflammatory action may be useful.

Olive leaf (Olea europaea) has become popular over recent years as a prophylactic and treatment for winter influenza, although little published research has appeared until recently (Micol 2005).

Propolis, the resinous material manufactured by bees from plants and rich in flavonoids, shows in vitro activity against various viruses (Adb El Hady 2002, Gekker 2003) and has proven immunomodulatory and anti-inflammatory effects including down regulation of inflammatory cytokine production (Ansorge 2003, Sa-Nunes 2003).

Various plants contain compounds which act as neuraminidase inhibitors in vitro in the same manner as oseltamivir (Liu 2008a, 2008b). The best studied of these is the flavone 5,7,4"-trihydroxy-8-methoxyflavone (Nagai 1990, 1995) which is closely related to baicalin and baicalein and found in roots of the popular Chinese herb baical skullcap (Scutellaria baicalensis) as well as aerial parts of the well known European skullcap (Scutellaria lateriflora).

Antiviral activity against SARS coronavirus has been reported for baicalin (Chen 2004) providing strong support for a potential role for baicalin containing phytomedicines in the treatment of acute H1N1 infection. The well established anti-inflammatory, antioxidant and antimicrobial activities of baical skullcap (Chuang 2005) would seem to support further research on this phytomedicine. With excessive inflammation in the lungs being strongly related to the virulence of pandemic influenza viruses, treatment of infected patients with anti-inflammatory drugs or herbal medicines may in some cases be useful. There could therefore be a use for anti-inflammatory phytomedicines or phytochemicals such as curcumin, a key constituent of the cheap spice turmeric (Curcuma longa) which is a significant inhibitor of TNF and could help reduce the adverse effects of excessive cytokine release.

Other expectorant, antimicrobial and anti-inflammatory respiratory herbs could be useful particularly as the majority of deaths from the 1918 pandemic occurred due to secondary bacterial pneumonia infection. These include plants such as elecampane (Inula helenium), white horehound (Marrubium vulgare), thyme (Thymus vulgaris), hyssop (Hyssopus officinalis), mullein (Verbascum thapsus), grindelia (Grindelia camporum), and polygala (Polygala tenuifolia).

Conclusion

While in all cases it is conjectural as to whether these or other various natural treatments would be helpful during an influenza pandemic, the seriousness of the situation warrants a systematic evaluation of these and other herbal medicines as possible alternative or adjunctive treatments to antiviral drug or vaccine therapy.

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Phil Rasmussen MPharm MPS DipHerbMed MNIMH(UK) MNHAA MNZAMH

Phytomed Medicinal Herbs Ltd, P.O. Box 83068 Te Atatu South Auckland New Ze aland

email: philr@phytomed.co.nz
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