WITHANIA: A USEFUL ADJUNCT WITH ANTIPSYCHOTIC MEDICATIONS

Antipsychotic drugs are strong medicines, and while they can successfully alleviate symptoms of psychosis and prevent relapse of schizophrenia and related conditions, like all drugs they are not without side effects.

There are two types of antipsychotics, older generation ones such as chlorpromazine or haloperidol developed in the 1960s, and so called ‘atypical’ antipsychotics such as olanzapine, clozapine and quetiapine developed in the 1990s, with a different side effect profile. While atypical newer generation antipsychotics are less likely than older generation ones to produce the extrapyramidal or Parkinson’s disease-like side effects, they can cause weight gain and precipitate or worsen metabolic syndrome or diabetes, and both types increase the risk of sudden cardiac death. Over-use and mis-use of antipsychotics is also of growing concern in the elderly(1).

Despite these risks, in a world in which the incidence and predominance of mental health conditions is rising, prescribing rates for antipsychotic drugs are increasing. Nearly seven million Americans take antipsychotic medications, and a recent study revealed a 49% rise in the use of anti-psychotic drugs by New Zealanders between 2008 and 2015. New Zealanders are now 60% more likely to be prescribed such drugs than Australians, with one in 36 New Zealand adults, or 2.81% of the population, being prescribed antipsychotic medication in 2015(2).

This recent New Zealand study also suggests that in a significant and probably increasing number of cases, these strong prescription-only drugs are being used to help with stress and associated sleep problems, rather than for their primary indication for conditions such as schizophrenia and bipolar disorders. Such ‘off label’ uses for prescription-only antipsychotics such as olanzapine, is something that has landed pharmaceutical companies in court in the U.S., in a number of prominent cases.

Herbal medicine offers an array of potential treatments for insomnia and stress-related conditions(3). One of the most suitable of these is Withania somnifera (Withania), known as Ashwagandha in India. The roots of Withania have a subtle but powerful nervous system and adrenal tonic action which insulates the nervous system from stress, enabling it to be better prepared to respond appropriately to the ‘fight or flight’ response. Many studies now support its applications for stress-associated anxiety conditions, including several human clinical trials(3).

Another possible application for Withania became apparent recently, through an American clinical trial where it was used as an adjunctive treatment alongside antipsychotic drug treatment in patients with schizophrenia(4). A total of 66 patients who had recently experienced an exacerbation of their schizophrenia symptoms, were given Withania or placebo alongside their usual antipsychotic drug medications, for a 12 week period. Outcomes were change from baseline to end of treatment on the “Positive and Negative Syndrome Scale” (PANSS), which measures total, positive, negative, and general symptoms of schizophrenia, and indices of stress and inflammation.

Patients given Withania were significantly more likely to achieve at least 20% improvements in PANSS negative, general, and total symptom scores, but not positive symptom scores, compared to those assigned to placebo. They also showed a significant improvement in stress scores compared to placebo. Additionally, only two of the Withania-treated subjects required an increase in their antipsychotic drug dosage, whereas nine of the placebo-assigned subjects either had their antipsychotic drug dosage increased or had a second antipsychotic drug added. These improvements were first noted at 4 weeks, and continued through the 12-week study period.

This is not the first time that Withania has been shown to be useful when taken alongside antipsychotic drugs. A one month clinical trial involving 30 schizophrenia patients with metabolic syndrome who had taken second generation antipsychotics for more than 6 months, found that adding Withania to their normal antipsychotic medication reduced serum triglycerides and fasting blood glucose, thus improving these metabolic syndrome symptoms(5).

Apart from Withania, clinical trials have shown appropriate doses of other high quality herbal medicines to benefit patients receiving antipsychotic drugs. Ginkgo was found to both increase the response rate to haloperidol when taken alongside it for 12 weeks(6), and to reduce the incidence of extrapyramidal side effects(7, 8). Similar effects have also been reported using Ginkgo alongside olanzapine(9).

Another U.S. study has shown American Ginseng (Panax quinquefolium) to have positive effects on memory function in individuals with schizophrenia, and to reduce the occurrence of extrapyramidal symptoms in patients on antipsychotic medications(10).

While underlying reasons for the high and increasing level of antipsychotic drug use in New Zealand and other countries should be further examined and addressed, clinical trials suggest that adjunctive herbal medicines such as Withania, Ginkgo and American ginseng, can play a role to help reduce some of the adverse events, and improve their response rates. Larger and longer term trials, are warranted.

References:
1. Bjerre LE; Canadian Fam Physician 2018; 64(1):17-27
2. Wilkinson S, Mulder RT. NZ Med J 2018 Aug 17; 131(1480):61-67.
3. Rasmussen PL, Feb 2017; Why Herbs should be the first choice of treatment for acute    anxiety. http://www.herbblurb.com
4. Chengappa KNR et al, J Clin Psychiatry 2018 Jul 10;79(5).
5. Agnihotri AP et al, Indian J Pharmacol 2013; Jul-Aug;45(4):417-8
6. Zhang XY et al, Psychopharmacology 2006; 188(1):12-17.
7. Zhang XY et al, J Clin Psychiatry 2001; 62(11):878-883.
8. Chen X et al, Psychiatry Res 2015; 228(1):121-127.
9. Atmaca M et al, Psychiatry Clin Neurosci 2005; 59(6):652- 656.
10. Chen EY et al, Phytother Res. 2012 Aug;26(8):1166-72

Herbs and Cancer

A diagnosis of cancer is a highly stressful experience and increasingly, a common reason for people to consult a medical herbalist. With ongoing environmental exposures to carcinogenic agents, genetic predispositions and aging populations, this is likely to continue in coming decades.

Pharmaceutical company expenditure on research into new cancer drugs far outweighs that spent on developing new antibiotics or antidepressants, and advances in diagnosis, surgery, chemotherapy, radiotherapy and other cancer treatments, continue to be made. These can be expensive however, and waiting lists unacceptably long, in an increasingly stressed healthcare system. Also, conventional medicine is not always effective in the treatment of cancer and in many patients, its adverse effects and a relatively poor risk versus benefit rationale, are reasons for exploring herbal and other natural treatments.

Consequently, there is a huge amount of material on the subject available online, in magazines and books, including websites offering cancer cures through expensive clinic programmes, or ‘ready to take’ products that are heavily marketed. Soon after informing friends, colleagues and family, newly diagnosed patients tend to be inundated with suggestions and recommendations to take a wide range of ‘herbal remedies’, ‘dietary supplements’, ‘superfoods’ and other ‘alternative treatments’, several promising a cure, and strongly advocating against conventional treatments.  Care should be taken with all of these.

It’s fairly well known that a large percentage of chemotherapeutic drugs for cancer and leukaemia treatment are molecules identified and isolated from plants or their synthetic equivalents or close derivatives. Research on herbs has led to the development of anti-cancer drugs such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide and more.

These are however, strong and individual chemicals found in or derived from plants, they are not the plants themselves. It is inappropriate to extrapolate from the anticancer effects of large doses of these drugs (often given by injection rather than orally), and to claim that a plant extract from which chemotherapy drugs have been developed will also exhibit significant anticancer properties. Also, successful traditional uses of most of these plants for the treatment (as opposed to prevention) of cancer in humans is in fact poorly established. Finally, the likelihood of something that kills cancer cells in vitro (in laboratory cultures) doing the same thing when taken orally by human patients, is actually pretty low, just as the diabetes drug insulin is poorly absorbed when taken orally, and needs to be administered by injection.

Of more relevance from a scientific evidence-based perspective, are herbs and natural products that show useful outcomes (efficacy) when used in studies involving rats and mice (rodents). We now know that the mouse and human genomes are approximately 85% identical, meaning that if something works in mice, it has a reasonable chance of also working in humans. A 2005 Canadian study that found daily oral ingestion of Echinacea purpurea root from the age of 6 weeks until death from natural causes (‘old age’) reduced the incidence of spontaneous tumours and prolonged the life expectancy of mice, is therefore highly relevant(1, 2). This type of study should be given more prominence than claims that oral administration of Madagascar periwinkle (Catharanthus roseus, the source of the anti-cancer drugs vincristine and vinblastine), can help fight cancer.

The best contribution that most herbs make is in fact related to their preventive effects against human cancers, just as a diet rich in vegetables and low in or excluding red meat is now well established to do the same. Well-known herbs and spices such as ginger, garlic, turmeric, rosemary, nasturtium and watercress, are just some for which compelling evidence now exists as to their prophylactic properties. Incorporating these and many others into the diet or taking as a tonic on a regular basis, is likely to help reduce the likelihood of developing many different types of cancer.

When it comes to management of patients with a cancer diagnosis, one of the most promising contributions that herbs can make, is as adjunctive treatments to be taken alongside the anti-cancer drugs and other conventional interventions that modern medicine now has available. Evidence from a large number of animal studies and a growing number of human clinical trials, now strongly supports this approach, key outcomes being to help increase the chances of achieving remission, and/or reduce the likelihood of treatment-related adverse effects such as infertility and fatigue. Sadly, however, most of my cancer patients don’t come to see me until either after they have undergone chemotherapy, or where it is no longer an option, and a small number firmly opt against conventional treatment. This is perfectly their right and completely understandable, but may not have been their decision if they had been informed of the valuable contribution an individualised concurrent herbal treatment regimen can sometimes make.

It is in fact a reflection of the widespread lack of acknowledgement and appropriate regulation of highly trained medical herbalists, that most people’s view of virtually all herbs and herbal products, is that they are only things to be sourced from ‘over the counter’ (OTC) or internet outlets. This is a far cry from their view of drugs, where when suffering from most debilitating or serious conditions, the prescribing expertise of a medical practitioner or specialist such as an oncologist, is sought prior to embarking upon drug treatments.

While proactive selfcare should be actively encouraged as the best preventive approach to cancer and other illnesses. However, once cancer is diagnosed, while herbs are rarely a magic cure, seeking the best professional advice rather than relying on google apps or recommendations from those not trained in herbal medicine, is highly recommendable.

 

Refs:

 

  1. Brousseau M, Miller Enhancement of natural killer cells and increased survival of aging mice fed daily Echinacea root extract from youth. Biogerontology. 2005;6(3):157-63.

 

  1. Miller Echinacea: a miracle herb against aging and cancer? Evidence in vivo in mice.

Evid Based Complement Alternat Med. 2005 Sep;2(3):309-14.

 

 

Medicinal Uses of Nasturtium

With spring upon us, the New Zealand countryside and our gardens are rich with budding and flowering plants, many of them normally regarded as weeds, but in fact highly medicinal.

One of these is Nasturtium (Tropaelum majus; Indian cress), a plant with water lily like circular leaves and bright yellow, orange and red flowers which is native to South America but established in many warmer areas of New Zealand and Australia. While it can certainly be very weedy in some situations, it also makes a useful plant on the edges of the vegetable garden to attract bees and other beneficial insects. It can also act as a decoy by attracting cabbage white butterflies and drawing these pests away from brassicas.

What many people don’t realise, however, is that all parts of Nasturtium are edible, with its leaves and flowers making a decorative, peppery addition to salads, and the fruits when pickled with vinegar serving as a tasty alternative to capers. It also has outstanding antioxidant activity due to its rich content of phenolic compounds, including anthocyanin and vitamin C. Like many ‘weeds’ readily available in the New Zealand environment, Nasturtium is also a highly medicinal plant.

Traditionally it was used to help ward off and treat various infections, particularly those affecting the lungs and the urinary tract. The pungent compounds known as isothiocyanates found in all parts of nasturtium and roots of horseradish (Armoracia rusticana), have powerful and fairly broad spectrum antibacterial activities particularly against Haemophilus influenza and Moraxella catarrhalis, a common cause of middle ear infection (otitis media) and sinusitus in children(1). These isothiocyanates have also recently been reported to have good activity against both developing and mature biofilms of Pseudomonas aeruginosa, a bacterial pathogen associated with many serious human illnesses(2). Importantly also, they have also been shown to be well absorbed into the bloodstream following oral ingestion of nasturtium in humans(3).

Nasturtium was used in folk medicine as a remedy against scurvy, and can be used as a natural, warming remedy to help the body overcome and prevent the common cold and influenza. It was also used traditionally to treat muscular pain, and it’s antimicrobial properties extend to its use as a topical treatment for bacterial infections and minor scrapes and cuts.

Possible applications in the prevention or treatment of various cancers are also likely, due to conversion of a key constituent glucotropaeolin to benzyl isothiocyanate, within the body. This compound, formed also from isothiocyanates found in brassica (cruciferous) vegetables, exhibits anticancer activity against cultured lung, breast, liver, prostate, brain, melanoma, oral & ovarian cancer cells in vitro, and prevents chemically induced carcinogenesis in rodents(4-10).

Potential benefits in fluid retention, hypertension and other cardiovascular conditions, have been suggested by Brazilian research showing diuretic, hypotensive and lipid-lowering activities for a hydroethanolic extract in rats(11-13). Angiotensin converting enzyme (ACE) inhibition was implicated as a possible mechanism for these effects, in a similar manner to how ACE inhibitor drugs work to help manage hypertension and other cardiovascular conditions(14). Unlike many other conventional diuretic drugs, however, no unwanted effects on urinary calcium or potassium excretion seem to occur, suggesting valuable potassium and calcium-sparing properties. These findings indicate possible applications also to help prevent osteoporosis, which is supported by another Brazilian study in menopausal rats(13).

Nasturtium may also be useful to help prevent or manage obesity, according to findings from a Korean study published in the June 2017 issue of the journal Food and Nutrition Research(15). The study investigated the effects of a nasturtium ethanolic extract on a mouse cell line with adipocyte-like characteristics, used in research on adipose (fat) tissue. Treatment of cells with nasturtium extract produced a concentration-dependent reduction in lipid accumulation, and inhibited the expression of various proteins associated with differentiation of fat cells. This suggests potential usefulness also, in the prevention and treatment of obesity.

With these compelling research findings, incorporation of nasturtium into the diet or herbal treatments of a range of human conditions common in the 21st century, should overtake our view of it simply as a bothersome weed.

References:

  1. Conrad A et al, Drug Res (Stuttg). 2013 Feb;63(2):65-8.
  2. Kaiser SJ et al, 2017 Jun;119:57-63.
  3. PPlatz S et al, Mol Nutr Food Res. 2016 Mar;60(3):652-60..See comment in PubMed Commons below
  4. Wattenberg LW. J Natl Cancer 1977 Feb;58(2):395-8.
  5. Hecht SS et al. J Nutr. 1999 Mar;129(3):768S-774S.
  6. Cho HJ et al, Int J Mol Sci 2016 Feb 22; 17(2):264
  7. Shang HS et al, Environ Toxicol 2016 Dec; 31(12):1751-1760.
  8. Yeh YT et al. Food Chem Toxicol. 2016 Nov;97:336-345.
  9. Zhu M et al J Cancer. 2017 Jan 15;8(2):240-248.
  10. Lai KC et al, Int J Oncol. 2017 Sep;51(3):832-840.
  11. Gasparotto Junior A et al. J Ethnopharmacol. 2009 Apr 21;122(3):517-22.
  12. Gasparotto Junior A et al. J Ethnopharmacol. 2011 Mar 24;134(2):210-5.
  13. Barboza LN et al, Evid Based Complement Alternat Med 2014; 2014:958291.
  14. Gasparotto Junior A et al J Ethnopharmacol. 2011 Mar 24;134(2):363-72. (2011a)
  15. Kim GC et al,.Food Nutr Res. 2017 Jun 14;61(1):1339555.

 

Antibiotics and their effects on Plants

Soil bacteria and fungi are a rich source of natural antibiotics, but the prevalence of human-made antibiotics and antibiotic resistance genes in soils, is an emerging concern. Antibiotics are widely used to promote livestock growth in modern non-organic agriculture, with poultry, cattle and pigs, being regularly treated with these antibacterial drugs. Millions of kilograms of antibiotics are released into the environment annually, much in the excrement of grazing animals, or through application of manure to agricultural fields(1). Discharge of human waste into waterways and the use of contaminated irrigation water or sewerage sludge to fertilise crops in many countries, is also a contributory cause. As a result, a higher level of antibiotic resistance is now apparent in conventional agricultural versus natural forest soils(2).

Soil and water-containing antibiotics constitute a potential route of human exposure to antibiotic resistance genes through their uptake by plants(3-8).  Uptake by plants can also have other effects, such as the accumulation of nitrofuran-type antibiotics in the edible parts of spring onions, and the subsequent metabolism of these into genotoxic and potentially carcinogenic hydrazine-containing metabolites(9).

The other consideration is the effects these human-made antibiotics have on the soil or plants themselves.  With human and animal health being intrinsically connected to that of plants and soil, and increasing research showing the many symbiotic and complex relationships between living organisms and their environment, effects of human-made antibiotics on plant health, should also be considered.

The high level of contamination with antibiotic residues and transferable resistance genes in pig manure applied to soil, has been shown to change the antibiotic resistant gene reservoir of the plant microbiome(10).  Carrots and lettuce can uptake amoxicillin and tetracycline(4), and tetracycline residues have toxic effects on both root and stems of germinating lettuce seedlings(11).  Oxytetracycline residues from cattle manure have also been shown to affect the diversity and type of nitrogen-fixing soil bacteria communities(12).

A recent European study has shown that even small amounts of antibiotics can have a range of potentially negative effects on plant traits(13). The comprehensive study examined the effects of three antibiotics (penicillin, tetracycline and sulfadiazine), on germination and growth of four plant species. These included two cultivated species (rapeseed, Brassica napus and common wheat, Tricicum aestivum), and two non-crop (herb) species (Shepherd’s purse, Capsella bursa-pastoria and Common Windgrass, Apera spicaventi). In farmland fertilised with manure containing antibiotic concentrations as typically found in agricultural soils, various effects on the plants were observed.

Main effects were delayed germination or reduced plant biomass. These effects varied markedly depending on the plant species concerned, but were most pronounced in the two herb species, particularly by penicillin and sulfadiazine. This suggests that different antibiotics could potentially affect the prevalence and types of species, and the diversity of natural plant communities near agricultural fields. Furthermore, these species-specific responses may not only alter the competitive abilities and makeup of the plant community, but also have secondary effects on other species such as pollinating and herbivorous insects(13).

Petrochemical residues and the use of non-organic agricultural pesticides and insecticides, are also starting to come under the spotlight as likely contributors to multi-drug antibiotic resistance among soil bacteria. A recent Chinese study has demonstrated that petrochemical residue -polluted soils were more than 15 times more likely than less-contaminated ones, to contain antibiotic resistance genes. This strong association of soil pollution with polycyclic aromatic hydrocarbons, suggests these may also be contributing to the growing amounts of antibiotic resistant genes in human-impacted environments(14).

In non-organic agriculture, soil bacteria can be continuously exposed to synthetic pesticides at sub-lethal concentrations, and a recent Indian study has found that insecticide-contaminated soil may have contributed to development of resistance to a range of different antibiotics, by several Bacillus species(15).

Silver nanoparticles are also now widely used in antibacterial products, and these inevitably discharge into aquatic environments and have been shown to affect the nitrogen cycle in phytoplankton and aquatic plant life(16).

Antimicrobial chemicals such as triclosan and triclocarban, which are used in some liquid soaps and toothpastes, can take a long time to break down in the environment and have been shown to have detrimental effects on aquatic organisms, and potentially contribute to antimicrobial resistance(17-19).

Soil and plant health are pivotal to the health of the planet and all its living organisms, and antibiotic drugs have saved many millions of lives. However, the widespread use of antibiotics in non-organic agricultural production systems particularly those involving animals, should be curtailed.

Refs:

  1. Popova IE et al, J Environ Sci Health B 2017; 52(5):298-305.
  2. Popowska M et al, Antimicrob Agents Chemother 2012; 56(3):1434-1443.
  3. Grote M. et al, Landbauforschung Volkenrode 2007; 57: 25-32.
  4. Azanu D et al, Chemosphere 2016; 157:107-114.
  5. Rahube TO et al, Can J Microbiol 2016; 62(7):600-7.
  6. Pan M et al, J Agric Food Chem 2014; 62:11062-11069.
  7. Kang DH et al, J AGric Food Chem 2013; 61:9992-10001.
  8. Kumar K et al, J Environment Qual 2005; 32:2082-2085.
  9. Wang Y et al, J Agric Food Chem 2017; 65(21):4255-4261.
  10. Wolters B et al, Appl Microbiol Biotechnol 2016; 100(21):9343-9353.
  11. Pino MR et al, Environ Sci Pollut Res Int 2016; 23(22):22530-22541.
  12. Sun J et al, Bioresour Technol 2016; 801-807, epub May 21.
  13. Minden V et al, AoB Plants 2017; 9(2):plx020.
  14. Chen B et al, Environ Pollut 2017; 220(Pt B):1005-1013.
  15. Rangasamy K et al, Microb Pathog 2017; 103:153-165.
  16. Jiang HS et al, Environ Pollut 2017; 223:395-402.
  17. Falisse E et al, Aquat Toxicol 2017; 189:97-107.
  18. McNamara PJ, Levy SB. Antimicrob Agents Chemother 2016; 60(12):7015-7016.
  19. Tremblay Louis, Environmental toxicologist, Cawthron Institute, Nelson, New Zealand Herald, 23 June 2017.

Manuka and Myrtle Rust

Last week I attended a two day workshop organised by scientists at Plant and Food Research Ltd and Massey University in Palmerston North, to discuss a range of recent scientific and biosecurity developments, concerning Manuka (Leptospermum scoparium), an important plant in New Zealand’s natural environment and economy. As with the two day Hui on ‘Manuka and More’ in Ruatoria and Te Araroa in November last year, this was an excellent event in which more than 30 scientists working actively on Manuka research presented on a diverse range of subjects and discussed where there could be gaps in our knowledge or research needs for this plant. While Manuka Honey and essential oil are currently the main two medicinal products produced from Manuka, numerous other therapeutic applications and potential contributions to preserving our environment, are found within this plant.

Jacqui Horswell and colleagues from the Institute of Environmental Science and Research, have shown that Manuka and other myrtaceaeous plants seem to be capable of killing the faecal bacterial pathogen Enterobacter coli (E. coli), by enhancing the die-off of this and other pathogenic organisms that pass through their root systems. A field trial involving riparian planting of Manuka is just getting going, to see whether laboratory results extend to helping to reduce animal effluent flows into a polluted lake. A lake which was once pristine and a treasured swimming area, but in recent years has changed into a green and dirty waterway due largely to dairy industry runoff, has been selected for this trial.

Hayley Ridgway from Lincoln University presented some interesting findings concerning novel and potentially useful mycorrhizae (fungi) and endophytic bacteria associated with the roots of Manuka, some of which I wrote about in my previous blog. Inoculation of Manuka plants with different mycorrhizae causes significant alterations in their growth rates and essential oil composition, highlighting the complex inter-relationships between microbes associated with Manuka, and its production of phytochemicals including some with bioactive properties.

Other presentations were made on experiences to date involving plantations of Manuka which have been established at a number of North Island sites in recent years. Challenges include site access, weeds, pests, and the relative attractiveness of different genetic lines to bees. A comment made by one of the presenters that while humans have had multiple generations of experience with cultivation and enhancing performance characteristics of crops such as wheat and rice, our experience with Manuka plantations spans less than 10-15 years to date.

The hottest topic at the workshop, however, was the recent finding of isolated outbreaks of Myrtle Rust (Austropuccinia psidii) in New Zealand nursery and garden grown specimens of Manuka and the native tree, Ramarama (Lophomyrtus bullata). This pathogenic fungi originated from Brazil where it causes guava rust, but spread internationally into North America in the 1880’s, and was first reported in Australia in 2010.  Australia is home to around half of the world’s Myrtaceae (Myrtle family) plant species, including Eucalyptus (850 species), Melaleuca (176 species) and Callistemon species.

Outbreak of Myrtle rust has had a devastating effect on much of the east coast as well as other areas of Australia, where it has resulted in ecosystem collapse for certain plant species. To date it has only been found in isolated locations in Northland, Waikato, Bay of Plenty and Taranaki, although it is widespread on Raoul Island in the Kermadec group, about 1,100km to the north-east of New Zealand.

Myrtle rust spores can easily spread across large distances by wind, or via insects, birds, people, or machinery, and it is thought the fungus arrived in New Zealand carried by strong winds and significant weather events from Australia.

The Myrtle Rust Strategic Science Advisory Group is working hard to assess and try to ameliorate the widespread environmental, economic, social and cultural impacts this plant pathogen could have on New Zealand. Apart from Manuka and Ramarama, other indigenous Myrtaceae species such as Pohutakawa (Metrosideros spp) and Swamp Maire (Syzygium maire), are under risk. Priorities including acceleration of scientific research into the biology of the pandemic strain detected here, pathways of spread, surveillance, management, exploring plant susceptibility and resistance, and coordinating and communicating a management plan that has widespread engagement by communities, scientists, industry and Maori stakeholders and landowners, councils and government.

The Ministry for Primary Industries (MPI) and the Department of Conservation (DOC), with the help of local iwi, the nursery industry, and local authorities are running an operation to determine the scale of the situation and to try and contain and control myrtle rust in the areas it has been found. However, emergence of the infection and appearance of the distinctive yellow or brown leaf discolouration may not become fully apparent until the spring, and a better assessment of the number of infection sites and their extent, may not be possible until then.

The arrival of Myrtle Rust in New Zealand means that the task of collecting and storing seed of New Zealand indigenous Myrtaceae including Manuka, has now become urgent. The NZ Indigenous Flora Seed Bank (NZIFSB), a collaborative project between Massey University, AgResearch, Landcare and the Department of Conservation, with support from the NZ Plant Conservation Network and the Millennium Seedbank at Kew in the UK, was established in 2013. NZFISB has been doing some really valuable work to collect and store seeds aimed at preserving a wide range of biodiversity within New Zealand native plant species. More than 130 volunteer seed collectors have been trained to date, and plans are underway to extend this and the level of community participation, to try to better protect our native plants for generations to come.

Refs:

http://www.nzpcn.org.nz/page.aspx?conservation_seedbank

http://www.mpi.govt.nz/protection-and-response/responding/alerts/myrtle-rust/

Antimicrobial Endophytes in Echinacea, Olive and Manuka

While plants are being extensively explored for new therapeutic properties and pharmacological activities, the communities of live fungi and bacteria known as endophytes that live between living plant cells, are also now being regarded as having many useful potential medicinal applications. Ironically, in recent years it is these microorganisms associated with plants rather than plants themselves, which seem to be receive much research interest.

Endophytes are microorganisms that live within a plant for at least part of their life cycles, without causing apparent disease or infections in the plant. Different endophytes seem to have affinities for particular plants, with which they have distinctive and cherished but complex interactions while each of them grows. They are for instance known to sometimes enhance host growth and nutrient gain, improve the plant’s ability to tolerate various types of stressors, and enhance the its resistance to insects and pests. The rrelationships that these bacteria and fungal communities have with their host plant varies from symbiotic to parasitic, to bordering on pathogenic.
Some very unusual and valuable bioactive substances are sometimes produced by these endophytes, such as alkaloids, phenolic acids, quinones, steroids, saponins, tannins, and terpenoids, and these are increasingly being recognized as sources of novel compounds which may help to maintain or solve not only the plant’s health challenges, but can also have applications in human and animal health problems.
Over the past few decades, some highly medicinal compounds produced by endophytic microbes lead to novel drug development. These include Taxol (paclitaxol), a complex diterpene alkaloid produced by the endophyte Metarhizium anisopliae found in the bark of the Pacific Yew (Taxus brevifolia) tree, and one of the most promising anticancer agents ever developed. Also streptomycin, an antibiotic produced from the bacterial endophyte Streptomyces.

Other endophytes possess antibacterial activities which may be useful in treating various infections, and in a world where antibiotic resistance is becoming a major public health threat, these are obviously of great interest. Exploring and bioprospecting these for potential antimicrobial compounds may well yield valuable new natural products or drugs to help in the fight against resistant organisms(1,2,3,4).

It now seems that bacterial communities colonizing Echinacea purpurea contribute to its well-known immune enhancing activity(5). American researchers have reported that Echinacea’s stimulating activity on monocytes (a type of white blood cell involved in engulfing and destroying harmful microbes), could be solely if not partially accounted for by the activities and prevalence of Proteobacteria, a family of bacteria found in the bacterial community associated with this medicinal plant.
A screen of 151 different endophytic bacteria isolated from three different compartments of Echinacea purpurea, revealed that several bacteria isolated from the roots are strong inhibitors of Burkholderia cepacia complex bacteria, a serious threat particularly in immune-compromised cystic fibrosis patients(6). One of these bacterial strains also showed antimicrobial effects against Acinetobacter baumannii, a pathogenic bacteria mainly associated with hospital-acquired infections, and Klebsiella pneumoniae, also increasingly incriminated in hospital infections(7). Interestingly, the type of bacteria and their antimicrobial effects varied considerably, according to which part of the plant (root, stem, leaves etc) they were associated with. This has resemblances to different plant parts of Echinacea having different phytochemical and thus pharmacological activities, such as Echinacea roots being richest in alkylamides and thus anti-inflammatory activities.

Endophytic fungi including Penicillium commune and Penicillium canescens (related to the Penicillium notatum mould from which the first antibiotic penicillin originated), have also been isolated from the leaves of olive (Olea europaea) trees, and several of these have also shown antibacterial as well as antifungal activities in recent work(8).

Finally, a rich endophyte community has recently been identified by Lincoln University researchers for the New Zealand native plant Manuka (Leptospermum scoparium). A total of 192 culturable bacteria were recovered from leaves, stems and roots, including some showing activity against the bacterial pathogen, Pseudomonas syringae pv. actinidiae(9), otherwise known by Kiwifruit growers as Psa. With Psa being a serious risk to the health of the Kiwifruit vine, it could be that these endophytic bacteria found within Manuka will make a useful contribution to ensuring the future health of the Kiwifruit industry.
While very few of all of the world’s plants have had their complete complement of endophytes studied, these are just three well established medicinal plants from which some highly active cohabitating bacteria and fungi have been sourced. Undoubtedly this area of research will receive much more attention due to growing concerns about antibiotic resistance, as there would seem to be a huge opportunity to find new and interesting endophytes among the wealth of different plants growing not only in soil, but also in waterways and oceans.
Refs:
1. Alvin A et al, Microbiol Res 2014; 169(7-8)L483-495.
2. Martinez-Klimova E et al, Biochem Pharmacol 2016; Oct 27.
3. Kealey C et al, Biotechnol Lett 2017; Mar 8 (epub ahead of print)
4. Tanwar A et al, Microbiol Path 2016;101:76-82
5. Haron MH et al, Planta Med 2016; 82(14):1258-1265.
6. Chiellini C et al, Microbiol Res 2017; 196:34-43.
7. Presta L et al, Res Microbiol 2017; 168(3):293-305.
8. Malhadas C et al, World J Microbiol Biotechnol 2017; 33(3):46.
9. Wicaksono WA et al, PLoS One 2016; 11(9):e0163717.

Why Herbs Should Be the First Choice of Treatment for Acute Anxiety

Anxiety can manifest in a wide range of ways. Apart from the internal emotional fearfulness, symptoms can include irritability, agitation, muscle tension, palpitations, sweating, insomnia, breathlessness, poor concentration, reduced socialisation and ability to undertake everyday activities. It is the most prevalent mental health disorder affecting children and adults, but many more people are dealing with problematic anxiety symptoms without any diagnosis.

In our increasingly changing world, where our daily exposure to stressful stimuli and life challenges can produce a rising barometer of worries, anxiety is often a major impediment to leading a fulfilling and happy life. Like most other health woes, humans have long pursued various practices to help overcome anxiety, the most popular of which is alcohol. Then there are drug medications, which have long been used to relieve anxiety, and remain widely prescribed.

Barbiturates were the first of these, sedative and anticonvulsant drugs which became popular particularly with sleep-deprived young mothers in the middle of last century, but which lead to the overdose deaths of thousands of people, including Elvis Presley and Marilyn Monroe. The next day ‘hangover effect’ from barbiturates was also always a problem, and development of a new chemical group of anxiolytic (anti-anxiety) and sedative drugs known as the benzodiazepines, lead to these superceding the barbiturates for the treatment of anxiety and insomnia. Benzodiazepines seem to act predominantly through stimulating GABA (gamma amino butyric acid) receptors in the central nervous system, and the commercialisation of Valium® (diazepam) by Roche in 1963 marked the start of a period during which this and other benzodiazepine drugs such as lorazepam, alprazolam and clonazepam began to be widely prescribed by GP’s and psychiatrists for anxiety and sleep difficulties. Between 1969 and 1982 Valium® was the most prescribed drug in the U.S., during which time Roche’s share price soared.

While safer than barbiturates, and effective as a ‘quick fix’ for anxious feelings or insomnia, safety concerns for benzodiazepines soon emerged. Feelings of fatigue, or a hangover the following day when taken as sleeping tablets, and a wide range of other side effects are all too common experiences. Most significant of these is the development of tolerance when they are used for more than a short period of time. As anyone who has been through it will testify, withdrawing from long term benzodiazepine use is a hugely stressful, unpleasant and often very protracted experience.

Feelings of depression can both contribute to or arise from excessive anxiety, and it is not uncommon for feelings of low mood and a low tolerance to stress, to be experienced together with anxiety. Apart from GABA, neurotransmitters such as serotonin, adrenaline and dopamine are intrinsically involved in influencing our emotions and mood, interacting together in complex ways that scientists still have little understanding of. It is therefore not surprising that many SSRI’s (selective serotonin reuptake inhibitor) drugs, used primarily as antidepressants, can have an anxiolytic effect in some people, and in many countries, these are often prescribed instead of or together with benzodiazepines, for anxiety conditions.

While sometimes effective as anxiolytics and less likely to produce adverse effects than most older generation tricyclic antidepressants, some find that SSRI’s can cause or increase anxiety feelings, or experience any one or more of a wide range of unpleasant side effects including insomnia, weight gain, emotional numbing or sexual dysfunction.

Another class of non-benzodiazepine sleeping tablets, the so-called  ‘Z-drugs’ such as zopiclone and zolpidem, have become popular in recent years, and while initially thought to be less habit-forming than benzodiazepines, they can also be very difficult to withdraw from after more than short-term use.

A large number of herbs have been traditionally used for nervous conditions and their anxiolytic effects, several of which have been shown in clinical trials to be beneficial as anxiety treatments. These include Chamomile, Skullcap, Passionflower, Valerian, Kava, Lemon balm and Withania.  Despite the number of well-designed trials undertaken to date being relatively low, and results sometimes variable depending on the particular herbal product(s) and dosages used, results are encouraging and in all cases show a better safety profile than for comparable anxiolytic drugs.

Of these, Kava (Piper methysticum), is the most studied, and is a non-addictive anxiolytic with great potential to treat anxiety. Its effectiveness in treating anxiety has been affirmed through several clinical trials and meta-analysis(1-3). While case reports of liver toxicity associated with kava usage lead to its restriction in some countries at the end of last century, use of the wrong plant part as raw material, or use in combination with alcohol or various drugs, were likely contributory factors. Also the frequency of such adverse events reports was substantially less than that for paracetamol, a commonly used analgesic.

Aerial parts of the herb Passionflower (Passiflora incarnata), have also been taken for anxiety for many centuries, and in a trial involving 36 outpatients with generalized anxiety disorder, it was as effective as the benzodiazepine drug oxazepam, but unlike oxazepam caused no impairment of job performance(4).

Roots of the herb Withania (Withania somnifera, Ashwagandha), have a subtle but powerful nervous system and adrenal tonic action, which insulates the nervous system from stress, and enables the adrenal glands to be better prepared to respond appropriately to stressful stimuli. A large number of scientific papers now support its applications for stress-associated anxiety conditions, including several recent human clinical trials(5,6).

While further studies involving greater participant numbers and longer term treatment are needed to identify optimal dosages and phytochemical makeup of the treatments involved, the fact that most herbal anxiolytic agents are safe and have the same or only a slightly higher incidence of adverse effects to placebo, is clear. It is therefore logical that before reverting to drug medications, more likely to produce unwanted adverse effects and in some cases long term dependency, herbal anxiolytics should be tried, in anxiety conditions.

Refs:

  1. Sarris J, Aust NZ J Psychiatry 2011; 45(1):27-35.
  2. Sarris J, J Clin Psychopharmacol 2013; 33(5):643-648.
  3. Savage K et al, Trials 2015; 16:493.
  4. Akhondzadeh S et al, J Clin Pharm Ther 2001; 26(5):363-367.
  5. Chandrasekhar K et al, Indian J Psychol Med 2012; 34(3):255-262.
  6. Pratte MA et al, J Altern Complement Med 2014; 20(12):901-908

Manuka & More

I recently attended a very interesting Hui (Gathering) in Ruatoria and Te Araroa on New Zealand’s East Coast, entitled ‘Manuka and More’.  Around 15 researchers from Crown Research Institutes and industry representatives including myself gave talks on subjects related to the NZ native tree Manuka (Leptospermum scoparium), which grows prolifically around the coast, and provides nectar for honeybees which produce manuka honey.  Manuka honey is being increasingly recognised as a highly active natural product with benefits as an antimicrobial and wound healer, and global demand for it has soared in recent years. Similarly the volatile oil of manuka has antimicrobial and anti-inflammatory properties, and is increasingly sought after.

manuka-4
Studies into what makes manuka honey so special, and characterisation of its many different chemotypes and genotypes, has been a focus of much research in the past decade. To the East Coast locals, manuka was once regarded mainly as a scrub plant and nuisance that was cleared to make way for pastural farming of sheep and cattle, but with honey prices continuing to rise and there being little money now in wool, manuka is being allowed to re-establish itself in many areas. Additionally, a lot of effort is now going into planting nursery-raised seedlings bred from chemotypes thought to produce optimal quality and yields of honey and oil.

With the plantation model being in its relative infancy, research into the potential effects of planted manuka on the local pre-existing chemotypes, and whether the yield of honey or oil will in fact be as high as hoped from these cultivated plants, is an area for ongoing investigation.

A growing number of local East coast people and Maori-controlled enterprises are now getting into the honey producing business, and the number of hives in NZ has nearly doubled from around 350,000 to 700,000 over the past 5 years. The sustainability of this level of honey production is another area requiring research, particularly as bees only feed off manuka (and kanuka) nectar for around 6 weeks each season. Monitoring their activities and ensuring they have sufficient food for the remaining 46 weeks of the year, is important.

Of the various flowering plants NZ honey bees feed off, Willow trees (Salix species), are an important source of pollen and protein for bees to feed their brood in the spring time, thus helping them to expand their population and gain maximum strength before the start of the honey flow season. Around the East coast a large number of willows grow particularly along waterways and on erosion prone areas. While the biggest problems for young willows are grazing animals and pests such as possums, rabbits and hares, an emerging pest is also the giant willow aphid which first appeared in NZ in 2013. Apart from infesting willow trees, this can boost the populations of wasps that attack honey bees.

smaller-leptospermum-scoparium-flower-manuka-flower-julyWhile not pleasing to all, other flowering plants such as the invasive introduced gorse (Ulex europaeus), presently plays an important role as a food source for bees in some areas. However, we should be planting other native species such as Hoheria (Hoheria populnea),  Whauwhaupaku or Five Finger (Pseudopanax arboreus) and many others, to provide pollen and nectar as a replacement for that from this imported thorny plant.

Other research presented at the Hui related to the role that mycorrhizal fungi, which grow on the roots of most plants, may have in ensuring the health of the manuka shrub. Most plants co-exist with these fungi, which help them better absorb nutrients from the surrounding soil, and can also help with disease prevention. Also monitoring for potential disease or infestation threats to Manuka such as Myrtle rust, a serious fungal disease not present in New Zealand, but which can affect other plants in the myrtle (Myrtaceae) family.

Recent studies suggesting that manuka seems to be useful at soaking up excremental pollution, and thus may be an ideal tree to plant alongside waterways polluted by effluent runoff from our overly intensive dairy industry, point to yet another exciting development in our understanding about this amazing native plant.

Overall, the range and quality of the diverse areas of research being undertaken, was most encouraging. This combined with the hands-on experience and traditional knowledge of the local Ngati Porou people who are increasingly finding meaningful employment opportunities from manuka-based businesses, gives great encouragement to the future social, economic and environmental wellbeing, of this beautiful area of New Zealand.

Manuka Oil as an Alternative to Antibiotic Creams

New Zealand has a higher incidence of Staphylococcus aureus infections than anywhere else in the developed world, and there has been a significant increase in the number of infections over the past decade, with Māori and Pacific children particularly affected.

manuka-flower-macro

Over usage of an antibiotic is likely to have contributed to this paradoxical increase in serious skin infections, according to results from a Health Research Council funded study. This revealed an increase in the prevalence of resistance in Staphylococcus aureus from 17% in 1999, to 28% in 2013. Dr Deborah Williamson, the clinical microbiologist who lead the study, made the statement in a recent press release that “The increase that we’ve seen in the incidence of serious skin infections in New Zealand children has happened at the same time as an increase in the dispensing of topical fusidic acid to treat skin infections”(1).

Fusidic acid is an antibiotic derived from the fungus Fusidium coccineum and was first released for clinical use in the 1960’s. A 2% fusidic acid cream is currently recommended as a first-line treatment for serious skin infections such as impetigo (school sores), infection of the hair follicles and boils. Most of these are due to the bacteria Staphylococcus aureus, including the notorious methicillin resistant Staphylococcus aureus (MRSA). Like all antibiotics, drug resistance can develop, and this is invariably at a rate proportionate to the extent of usage.

In a paper published in the New Zealand Medical Journal last December, Dr Williamson reviewed the history and usage of topical antimicrobials in New Zealand (2).

This painted a somewhat alarming picture, and the fusidic acid story is an all too familiar one. Another topical antimicrobial agent widely used throughout the 1990s, mupirocin (Bactroban©), was for many years made available to purchase ‘over-the-counter’ (OTC). This led to high levels of use, and subsequent high rates of resistance, and by 2000, approximately 14% of S. aureus isolates displayed high-level resistance to mupirocin(3) . From April, 2000, regulatory changes lead to mupirocin being restricted again to ‘prescription only’, and the resulting decreased usage lead to a fall in the prevalence of high-level mupirocin resistance in S. aureus from 14.2% in 2000, to 8.3% in 2014 (4).

New Zealand is not alone in having a high rate of bacterial resistance to topical antimicrobials, and resistance to antibiotics poses a major global threat, according to a 2014 report by the World Health Organisation(5). Resistance is happening in every region of the world, and unless some major developments take place soon, humankind could be heading towards a time when once again, antibiotics cannot be relied upon to protect against simple infections including those that are risk factors associated with surgery. Development of strategies to mitigate further increases in antimicrobial resistance to topical treatments, is urgently required(6, 7).

Key to this, should be effective wound management. This should combine mechanical-chemical procedures such as debridement, antiseptics, and antimicrobial supportive compresses to help remove the biofilm (an association of microbes and slime which adheres to the surface of the wound, delaying granulation tissue formation and migration of epithelial cells).

Limitation of the level of usage of drug-based antimicrobials, or using two or more of them together rather than alone, and avoidance of topical antibiotic use in common conditions such as acne, are other ways to help reduce the likelihood of resistance(8).

Plants contain a large number of diverse chemicals (phytochemicals) which they produce as defence tools to enable them to survive in their particular environment, and some of these have potent antibacterial activities which can help us fight a wide range of common skin infections.

manuka-2The New Zealand native Manuka (Leptospermum scoparium) is one of these, and the ability of certain forms of Manuka Honey to act as potent healing agents for wounds and ulcers, is becoming increasingly recognised(8). Many clinical trials have now shown manuka honey dressings to have unique healing properties in chronic leg ulcers and other stubborn skin infections, and synergistic antimicrobial activities with various antibiotics, have recently been reported(10,11).

Manuka’s medicinal properties extend way beyond those of the honey that bees manufacture from its pollen, however, and other parts and extracts of this wonderful plant, have therapeutic activities. Manuka essential oil has also been shown to exhibit powerful antimicrobial properties, particularly against Staphylococcus aureus and other Gram positive bacteria, yeasts such as Candida albicans and fungi such as Trichophyton rubrum, responsible for athletes foot. Manuka oils which are rich in beta triketone compounds, appear to have the strongest antimicrobial activity.

The extent to which topical application of an extract of this plant can rival drug-based treatments at overcoming sores, was highlighted by a research project by two students at Whangaroa College in Northland recently. After hearing about a fellow student’s spider bite that wouldn’t heal until it was treated with a native plant preparation, the two students, Cheyenne Rush and Georgia Mills, decided to investigate the antibacterial properties of manuka essential oil and an extract of another native plant kawakawa (Macropiper excelsum).

Their experiment, which they entitled Te Rongoa Māori , involved collecting and growing colonies of bacteria, spreading these onto agar plates and applying a quarter of a teaspoon of each product to be tested. The relative rates of decline of the bacteria was recorded daily for 14 days, for the manuka oil and kawakawa extract preparations, in addition to the well known antiseptics Savlon® and Betadine®, which were applied to other agar plates as controls.

The results showed that manuka oil was the most powerful antibacterial, followed by Savlon® then Betadine®, with the Kawakawa leaf extract the least effective. Cheyenne and Georgia’s project thus showed that a simple, traditional plant preparation can be more effective than prominent antiseptic products in fighting wound colonising bacteria. It also won them a top prize at the recent Top Energy Far North Science and Technology Fair, which involved more than 150 participants from 10 schools in upper Northland(12).

Refs:

  1. Media Release from the Health Research Council, Soaring rate of skin infections linked to resistance.NZ Doctor, 20 September 2016.
  2. Williamson D et al, A bug in the ointment: topical antimicrobial usage and resistance in New Zealand. NZ Med J 2015; 128(1426):103-9.
  3. Upton A et al, Mupirocin and Staphylococcus aureus: a recent paradign of emerging antibiotic resistance. J Antimicrob Chemother. 2003; 51:613-617.
  4. Heffernan H et al, Demographics, antimicrobial susceptibility and molecular epidemiology of Staphyloccosu aureus in New Zealand, 2014. https://surv.esr.cri.nz/PDF_surveillance/Antimicrobial/Staph/2014Saureussurveyreport.pdf
  5. Antimicrobial Resistance: Global report on surveillance. World Health Organisation, who.int.ISBN 978 92 4 156474 8; (http://www.bbc.com/news/health-27204988).
  6. Williamson D et al, Missing in action: an antimicrobial resistance strategy for New Zealand. NZ Med J, 2015; 128(1427):65-67.
  7. Williamson DA, Hefferman H. The changing landscape of antimicrobial resistance in New Zealand. NZ Med J 2014; 127(1403):41-54.
  8. Walsh TR, The Lancet Infectious Diseases, 2016; 16(3): 23-33
  9. Carter DA, Front Microbiol 2016; 7:569
  10. Muller P et al, PLoS One 2013; 8(2):e57679
  11. Liu M et al, Front Microbiol 2015; 5:779.
  12. https://ssl-www.stuff.co.nz/auckland/local-news/northland/83909327/Manuka-proves-best-bacteria-fighter