Peony: A Reference for Patients and Practitioners

Peony A Reference for Patients and Professionals

Stuart FitzSimons

Peony A Reference for Patients and Professionals

Stuart FitzSimons

Every now and again, a herb will emerge from the world of the herbal clinic and find its way to public attention. Just such a herb is peony.

Introduction In the world of herbal medicine there are some well known and high grossing products available over the counter at health food stores and pharmacies. Some of these herbs are now household names.

Echinacea, Ginkgo, and St. John’s wort are great examples of such herbs that have been promoted so heavily that they are now effectively mainstream household remedies. However, in terms of the number of herbs in use by herbalists in their clinics these popular herbs don’t even scratch the surface.

More interestingly, there are herbs in use in the clinics of herbalists that would literally blow the commercially popular ones out of the water in terms of their actions and effects. I often wish people realised just how many herbs there are out there with histories of use that make drugs look foolish by comparison. However, we are now in a period of time when legislation rules the roost and to bring a herbal medicine to the market requires a lengthy and costly process.

Every now and again, a herb will emerge from the world of the herbal clinic and find its way to public attention. Just such a herb is peony, truly one of the best kept secrets in the herbal world!

This is a herb with centuries of continuous use and a record of success and safety that beggars belief. Peony has always been one of my favourite herbs and it has been a mainstay of my dispensary for nearly 30 years and, at last, I am glad to say this incredible secret from the herbal world is now emerging into the spotlight and I look forward to it becoming a firm fixture in the lives of many people who will benefit immensely from its use.

This booklet was written with both the herb using public and professionals in mind. You may find some of the detail a little heavy going for you. Simply, skip through to the section that interests you as I hope you’ll find everything you need to know about the use of peony as a medicine on these pages.

Stuart FitzSimons

(MNIMH Dip. Phyt; Medical Herbalist)

PEONY – A Reference for Patients and Professionals

PEONY - A Reference for Patients and Professionals Published by plantasmagorical. UK ISBN - 978-0-9574238-2-4 Š 2015 plantasmagorical Warning-Disclaimer This book is designed for educational purposes only, to provide information in regard to the subject matter covered. It is not intended to be a substitute for informed medical advice, diagnosis or medical treatment. You should not use the information in this book to diagnose or treat any health problems or illnesses without consulting your health care practitioner. Neither the publisher or the author can accept liability or responsibility for the use or misuse of any of the materials or methods recommended in this book or for any consequences arising directly, indirectly or allegedly out of their use.

Licence Statement All Rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publishers and the author.

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PEONY – A Reference for Patients and Professionals

Contents Page Origins of the name “peony” and other names for the plant

5

Botanical description of Paeonia lactiflora 5 Peonies everywhere and everywhen!

7

Traditional and historical medicinal uses of peony

10

Peony in “Traditional Chinese Medicine”/ TCM

13

Constituents of Paeonia lactiflora

17

So what have peonies been used to treat?

25 Menopause 25 Dysmenorrhoea (period pain) 27 PMS/PMT 28 Menorrhagia (heavy periods) 29 Polycystic ovarian syndrome/PCOS 29 Post natal problems 32 Epilepsy 32 Peony as an anti-inflammatory 36 Skin diseases 42 Miscellaneous 44 A word on combining peony with other herbs

45

Checklist for the best use of peony

47

What is the dosage of the peonies?

48

Are there any side-effects of peony? Can it be taken

with other medicines?

48

References 49 Index 63

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PEONY – A Reference for Patients and Professionals

The Chinese name for peony is Sho Yu, meaning Most Beautiful.

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PEONY – A Reference for Patients and Professionals

Origins of the name peony and other names for the plant P. albiflora Pall., P. edulis Salisb In Chinese: Sho Yu (Most Beautiful) The plant is named after “Paeon”, who was a student of Asclepius in Greek mythology and became the physician of the gods. Paeon however made his teacher angry and Asclepius threatened Paeon with death. Fortunately, Zeus intervened, and to spare Paeon from Asclepias he turned Paeon into a flower, the peony!

Even though peony is a plant famed for it flowers the part used in herbal medicine is the root. Having said that, in the past, the flowers, seeds, leaves and roots have been used, but today it is the root alone that is used.

Botanical description of Paeonia lactiflora A perennial herb (a plant that re-grows every year from its own root stock or older stems) that grows between 50-80 cm in height. The flowers are large, about 5-10 cms in diameter and have 5-10 petals that are white to pink.

In the centre of the flower there are numerous yellow stamens and pollen bearing anthers. They are propagated by root division, or rarely, from seed.

Peonies, strictly speaking, belong to the Paeoniaceae family (first suggested in the 1830’s) although they are still commonly listed by some as being members of the Ranunculaceae (buttercup) family.

The World Health Organisation provides the following pharmacognostical description of Paeonia lactiflora1: Paeonia lactiflora Pallas is a perennial herb, 50–80 cm high, with a stout branched root. Leaves alternate and biternately compound, the ultimate segments red veined, oblong-elliptical. The leaflets are narrowovate or elliptical, 8–12cm long and 2–4 cm wide. The petioles are 6–10 cm long. Flowers large (5–10 cm in diameter), solitary, and red, white, or purple. Sepals 4, herbaceous, persistent. Petals 5–10, larger than sepals. Stamens numerous and anthers yellow; carpels 3–5, many-seeded. Fruit, 3–5 coriaceous few seeded follicles. Seeds large, subglobose; testa thick.

1.

WHO Monographs on Selected Herbs – Vol 1. 1999

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PEONY – A Reference for Patients and Professionals

Plant material of interest: dried root.

General appearance Radix Paeoniae is cylindrical, straight or slightly curved, two ends truncate, 5– 20 cm long and 1–2.5 cm in diameter; externally light greyish brown to reddish brown, glossy or with longitudinal wrinkles, rootlet scars and occasional remains of brown cork, and with laterally elongated lenticels; texture compact, easily broken, fracture relatively even, internally whitish or pale brownish red. Cambium ring distinct and rays radial.

Organoleptic properties Odour, slight; taste, slightly sweet at first, followed by a sour or astringent taste and a slight bitterness.

Microscopic characteristics Literature description not available; to be established in accordance with national requirements.

Powdered plant material Light greyish brown powder; masses of gelatinized starch granules fairly abundant, 5–25 μm in diameter; clusters of calcium oxalate 11–35 μm in diameter, packed in parenchyma cells in rows or singly; bordered, pitted, or reticulate vessels 20–65 μm in diameter, walls thickened and slightly lignified.

Geographical distribution China, India, and Japan.

General identity tests Macroscopic, microscopic, and microchemical examinations; thinlayer chromatographic analysis for the presence of the monoterpene glycoside paeoniflorin.

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PEONY – A Reference for Patients and Professionals

Peonies everywhere and everywhen!

As the keen gardener will know there are an awful lot of plants referred to as peony. There are 35-50 species of peony belonging to the Paeoniaceae family.

They are much loved by horticulturists because of their spectacular blooms and they are commonly seen in parks and gardens with many varieties being easily obtained through garden centres and specialist breeders. Thankfully, from the medical perspective we can narrow down this huge family to three peonies in particular. The three peonies used in herbal medicine nowadays are most commonly used in the Chinese system of medicine, they are: – Red peony (Chi shao yao) – White peony (Bai shao yao) – Moutan/tree peony (Mu dan pi) Red and white peony in this herbal context basically refers to slightly different preparations of the the same species, i.e. Paeonia lactiflora Pall. The colours refer to the processed root itself rather than the colour of the flower the plant produces. Chi shao yao is the whole root, whilst bai shao yao has had the root bark stripped from it after it has been boiled. The bark of the root, as is found with chi shao yao, obviously contains more active constituents than the root without bark, as in bai shao yao, and this difference leads to the slightly differing applications for each variety of the root. I would always prefer chi shao yao because of the wider spectrum of active constituents.

Moutan peony is correctly known as Paeonia suffruticosa. As we can see from the nomenclature above red peony is known in Chinese as chi shao yao, and white peony is called bai shao yao. To be even more technical, chi shao yao can be derived from P. lactiflora or P. veitchii Lynch, but bai sho yao can only be derived from P. lactiflora. In reality however, all chi shao yao

Chi shao yao

Bai shao yao

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PEONY – A Reference for Patients and Professionals

White peony (Paeonia lactiflora Pall.)

and bai sho yao is derived from P. lactiflora. Even though they are the same species they are classified differently, although in a complimentary fashion, in Chinese medicine, and they have slightly different applications.

Historically speaking, bai shao yao and chi shao yao have not always been separate items. For example, if we go back to the Han Dynasty (206 BC 220 AD), we find traditional Chinese medical texts only mentioning “Shao Yao”. One of the first mentions of a specific difference between chi shao yao and bai shao yao occurs in a version of one of the great Chinese medical texts called the “Shen Nong Ben Cao Jing” which was compiled in the sixth century AD. Gradually, from this point, the two become further defined and clarified in terms of their individual uses, and by about 960 AD the two are found as distinct pharmaceutical entities. By the eleventh century there are references to the widespread cultivation of “Shao Yao”, showing that, up to the modern era, there has been a demand for this important medicine for at least the last millennium!

To further add to this “colour” confusion it is worth noting that Paeonia lactiflora is actually listed in the most official and important drug book in the UK, The British Pharmacopoeia. It is listed as “White Peony Root”. The white in this case refers to the proper name, i.e., lactiflora, which is Latin for “white flower”! In The British Pharmacopoeia there are two types of Peony listed: 1. Processed White Peony Root which is defined as: White Peony Root that has been boiled, peeled and dried. It contains not less than 1.6% of paeoniflorin (C23H28O11), calculated with reference to the 8

PEONY – A Reference for Patients and Professionals

Moutan peony (Paeonia suffruticosa)

dried material. It is collected in summer and autumn, washed clean, with the two ends and rootlets removed, either peeled after boiling in water or boiled in water after peeling and dried in the sun. The dried root is washed and soaked thoroughly prior to being sliced transversely or longitudinally and dried.

2. White Peony Root which is defined as: The dried whole root of Paeonia lactiflora Pallas (Paeonia albiflora Pallas; Paeonia edulis Salisb.; Paeonia officinalis Thunb.). It contains not less than 1.6% of paeoniflorin (C23H28O11), calculated with reference to the dried material. It is collected in summer and autumn, washed clean, with the two ends and rootlet removed and dried.

In other words, 1. is bai shao yao and 2., is chi shao yao.

The Romans were probably the first people to spread peonies around Europe (from a homeland in south eastern Europe) and a few varieties became popular not just for their blooms and perfume but for their medicinal qualities. As we will see shortly, in Europe peony was given the botanical name, Paeonia officinalis. Any plant with ‘officinalis’ in its name is a herb that was an “official” medicine. However, the first properly recognised and botanically described sample of Paeonia lactiflora from China arrived at Kew Gardens in 1784 and was sent by Peter Pallas (a German zoologist and botanist 1741-1811) to Sir Joseph Banks (Head of the Royal Botanic Gardens). When we see the botanical name of Paeonia lactiflora Pall. written in full like this, then we can see the ‘Pall’ is there as a citation to Peter Pallas.

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Traditional and historical medicinal uses of peony If we take the Chinese and Ayurvedic (Indian) use of peony as a medicine into account then we have well over a millennium of constant use of this herb. As we have seen though, when it arrived in Europe it quickly became an “official” medicine and some of the great physicians and scientists from the ancient European world have described its use. The ancient Greek and Roman scholars Dioscorides, Pliny and Galen for example were all aware of the use of peony as a medicine, and even went as far as to describe and use a male (Paeonia mascula) and female (Paeonia officinalis) type of peony.

In fact, one of the rarest wild plants in the UK today is Paeonia mascula, being found only on the island of Steep Holme in the Bristol Channel. It was thought to have been introduced to the island by monks in the fourteenth century and was cultivated because of its use as a medicine. Both P. mascula and P. officinalis are considered very close relatives of P. lactiflora.

It is interesting to see what Dioscorides had to say about the use of Peony.

Dioscorides was a doctor in the army of the Emperor Nero and lived between 40-90 AD. His medicine was all about keeping an army going, any useless remedies therefore were binned! With the army he traveled extensively and got to study and document many herbs, medicines and treatments from the ancient world. Dioscorides is responsible for compiling one of the most important medical texts of all time, De Materia Medica. In fact, De Materia Medica remained an important text until the nineteenth century and you can see its influence in the work of the famous British herbalists such as John Gerard (1545-1612) and William Turner (1508-1568).

According to Dioscorides: “the root of peony is given to women who are not cleansed after childbirth. It stops excessive bloody discharges in women. It is good for the suffocation that comes from nightmares and for the suffocation of the womb. Disorders of pregnancy are eased by peony and it can help to induce menstrual flow. It works against fevers that are associated with shivering, pain in the intestines, jaundice, inflamed kidneys and pain in the bladder as well as easing discharge of the bowels.”

As we can see, peony, in ancient times, would definitely come under the heading of a menstrual or gynaecological herb and we see something of its 10

PEONY – A Reference for Patients and Professionals

“cooling” effect. Another interesting observation is that it is suggested as a treatment for nightmares and over the centuries this calming or sedating effect is repeated and we see it being suggested for epilepsy in children.

Just to make life a little more complicated; the Ayurvedic physicians of India used Paeonia emodi (Himalayan Peony) in their system of medicine to treat epilepsy and gynaecological disorders. Dr. Nadkarni’s Indian Materia Medica states: “Roots of this plant are reputed to be blood purifier and antispasmodic, an esteemed remedy in colic, uterine disorders, epilepsy, bilious obstruction, convulsions and hysteria. The root is given to cattle to render them prolific.”

The Europeans used Paeonia officinalis for similar purposes. An old British herbal2 by Dr. M. Robinson for example, states: “Male peonies are the best; the roots have more virtue than the seed; next the flowers and then the leaves. The roots fresh gathered, cure the falling sickness. The roots powdered are excellent for hysterical and nervous complaints. A decoction of the root is very cleansing immediately after childbirth. It also drives away melancholy and nightmares.”

The term “falling sickness” is the old fashioned term for epilepsy or seizures.

It is interesting to note that the term “hysterical” in olden times referred specifically to the type of psychological upsets that happened along with menstrual conditions such as PMS etc. The word “hysterical” is derived from the ancient Greek word “hystos”, meaning womb (it’s where words such as hysterectomy come from). In fact, in days gone, by the womb was not only blamed for causing all manner of problems but was actually thought to almost have a mind of its own and to be able to move around inside the abdomen under its own volition! It is also worth stating that I am not referring to ancient Chinese or other more obscure cultures here, but Europeans from the Victorian era, for whom “furor uterinus” (literally, agitation of the womb) was a commonly used diagnosis to cover all the disturbances, including psychological symptoms, arising from conditions of the womb.

Hystos and hysteria would have been terms far more acceptable to Victorian society than talk of genitals or the menstrual cycle etc. What I am trying to 2.

The New Family Herbal and Botanic Physician, M Robinson, MD, 1900

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demonstrate here of course, is that whilst we know what hysterical means to us today, it, and other terms used in old fashioned and now obsolete medical terminology, may have had far more precise and interesting meanings than we now realise.

The use of Paeonia officinalis is also described by the great American Eclectic physicians. The plant was taken to America by European settlers. The Eclectics had this to say about peony: “Peony is antispasmodic and tonic. It is asserted to have been successfully employed in chorea (a kind of persistent nervous twitch), epilepsy, spasms, and various nervous affections. In combination with white snakeroot, or black cohosh, it has proved valuable in pertussis (whooping cough). Doctors Felter & Lloyd “The agent is an antispasmodic. Through a mild but persistent tonic influence, it is soothing to the nervous system of debilitated patient and of the aged. It is curative wherever there is irregular muscular action. It is useful in chorea; either alone or combined with other positively indicated remedies. It has been given with good results in convulsions of childhood, and other convulsive phenomena, and its persistent use in epilepsy has resulted satisfactorily in some cases. It is not a powerful remedy, but it is one that has a steady and persistent influence, and will therefore be found of use as auxiliary to the action of positive but temporary remedies”. Finley Ellingwood M.D. 1919 Antispasmodic is a word used to describe a herb that reduces muscle spasm.

Whilst today this term is used almost exclusively to refer to the treatment of spasms in the gut, in traditional herbal circles it is used to refer to a remedy that might relieve spasm of muscles in several areas, the bladder and the womb for example. It is interesting to note that above we see the combination of peony and black cohosh, another herb that has found fame for its gynaecological/menstrual applications.

As we see, these different traditions do seem to be in quite close agreement as to the medical uses of peony. We could divide what we have covered so far into two particular areas: gynaecology and epilepsy.

We will see, a little later, how close the “old timers” were to what modern research on peony has found. Generally though, we can safely say that peonies have been used world-wide in traditional healing systems for millennia, but it is in traditional Chinese medicine that they are truly tested, examined and defined in critical detail, and so we will take some time now to examine the Chinese use of Peony.

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PEONY – A Reference for Patients and Professionals

Peony in traditional Chinese medicine (TCM) Red peony (chi shao yao) is classified in traditional Chinese medicine as an herb that ‘invigorates the blood’. White peony (bai shao yao) is classified as an herb that ‘tonifies the blood’. Moutan peony (mu dan pi) is classified as an herb that ‘cools the blood’. I shall talk about all three types initially, as it is interesting to see how they are used very similarly.

So, what is all this talk about “blood”? Is this blood as we know it or another concept entirely? Let’s examine this concept and discover how Peony fits in with all this.

Blood in the traditional Chinese system of medicine should not be taken to mean the same as the actual fluid we in the west call blood. Rather, it is an energetic concept.

The traditional Chinese view of blood, specifically as applied to women, is that it is the expression of the basic constitutional strength of the woman.

Although this energy flows all over the body the major store of blood, and therefore the seat of strength of a woman, is the womb. If the blood becomes

Peony is a herb with centuries of continuous use and a record of success and safety that beggars belief.

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PEONY – A Reference for Patients and Professionals

weak or deficient the symptoms are pallor, dizziness, lethargy, palpitations, dry skin, menstrual irregularities and a fine pulse. This state of affairs would be remedied by using the herbs that ‘tonify the blood’ such as white peony.

If on the other hand ‘blood’ becomes stagnant (or, if this vital energy flow is impeded) the symptoms that arise consequently include pain and masses, particularly in the female reproductive tract and abdomen. A mass refers to any kind of lump, things like cysts, fibroids, abscesses and even tumours.

This situation is remedied by applying the herbs that “invigorate the blood”, such as red peony.

As we saw, the blood reflects the woman’s basic constitutional strength or “essence”. The womb is the seat of this blood and strength, a reflection of the capacity to create and nurture a new life within. The heart on the other hand is the seat of the spirit, also called “shen.” Every month, the heart, which is connected to the womb by a special channel, the “bao mai” sends blood down to the uterus. This blood and the essence it contains either helps manufacture a new life, if conception occurs, or is shed as “heavenly water” if menstruation occurs. After seven times seven years the essence is exhausted and the woman’s body no longer has the capacity to produce and shed menstrual blood and the menopause ensues. At this point, rather than sending blood down from the heart to womb the flow is reversed, and blood flows upward to nourish the spirit. So the menopause is not seen as a loss of youth but rather a time when the spirit is nourished and wisdom is consolidated. Those of you who have had that classic comment from your doctors, ‘it’s your age love’ will now realise, in light of what we have just said, just how pathetic, ignorant and historically unique this modern western attitude to menopause is.

The use of the term “heavenly water” above is again a real term used to denote the respect shown to the female body in it’s role as the vessel of transformation and re-generation. By comparison, an old Sanskrit term from India to describe menstrual blood is “kundapuspa”, “the flowers of the sacred well”. Unfortunately, the first four letters of “kundapuspa” have also given risen the most disgusting four letter word in use today! Man has a gift for destroying everything it seems.

Further definition of the Chinese use of peonies

If we take a closer look at a more in depth description of the peonies from a typical Chinese materia medica3, their applications become even clearer: 3. A materia medica is a dictionary of medicines

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PEONY – A Reference for Patients and Professionals

Red peony (chi shao yao) Invigorates the blood and dispels blood stasis.

For dysmenorrhoea (painful periods), amenorrhoea (no periods), abdominal pain and immobile abdominal masses. Also for the swelling and pain associated with traumatic injury (such as post-operatively), and the early stages of abscesses and boils. Clears heat and cools the blood. Also for gynaecological problems associated with hot blood.

White peony (bai shao yao) Nourishes the blood and regulates the menses.

For blood deficiency with such symptoms as menstrual dysfunction, vaginal discharge and uterine bleeding. This is an herb very commonly used for women’s disorders. This herb stops painful spasms in the abdomen. It is also used for yin deficiency where the yang floats to the surface causing spontaneous sweating and night sweats.

White peony is commonly used for women’s disorders.

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PEONY – A Reference for Patients and Professionals

Moutan peony (mu dan pi) Clears heat and cools the blood.

Also for frequent and profuse menstruation due to heat in the blood.

Invigorates the blood and dispels blood stasis. For liver blood stasis patterns with amenorrhoea, abdominal masses, lumps or bruises due to traumatic injury. For such symptoms as flushing and dysmenorrhoea.

Even though the language used is a strange mixture of traditional Chinese terminology and modern western terminology, the situation is clear. Here we have, in three herbs, a sort of all round, total care package for women at all stages of menstrual life and we begin to understand the concept of how peony can be used to “cool the blood” or “dispel heat” caused by menstrual/gynaecological problems.

Just to define more clearly this “cooling” effect of peony, we have to be aware that in Chinese medicine this effect will be used to treat heat and flushing that might accompany any condition, not just menstrual/gynaecological conditions. For example, peony is a pivotal herb in the treatment of eczema and other hot, irritated skin conditions. It is also used to bring down fevers that occur as part of infections or inflammatory disorders, and it is particularly important in the treatment of children who may have fits or seizures when they get a fever!

Peony is often applied to bring out rashes and thus hasten the resolution of infections, and we can begin to see why peony is potentially very useful in the treatment of hot flushes and night sweats that often occur as part of the menopausal symptom picture.

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HO

Constituents of Paeonia lactiflora (Chi shao yao/Bai shao yao)

O H C

CO CH2

O

O O

OverO260 chemical compounds have been isolated from the peony family but CH2OH the main constituents of Paeonia lactiflora are paeoniflorin, albiflorin and O O H pentagalloylglucose.

H OH

H H

OH H

O HO

O O

OH

OH

O

O O

OH OH

C

OH

OH

CH3

H

Fig. 1. The chemical structure of Albiflorin

Another important and highly active chemical from the Peony family, paeonol, is present in Paeonia lactiflora, but this chemical is found in much higher quantities in Paeonia suffruticosa and is only found in low quantities in Paeonia lactiflora4.

HO

O O

O

H C

CO CH2

Fig. 2. The chemical structure of Paeonol CH2OH

H

O

O

Paeonol has been shown to exhibit anti-inflammatory, pain-killing and H H OH anti-allergy effects. It was one of the components that came under the H OH on children with spotlight when Chinese herb trials were carried out eczema/dermatitis at GreatO Ormond St Hospital in the earlyH1990’s.OHAt one point paeonol was thought to be one of, if not, the most active component HO in this multi-herb formula.

O O 4.

O Yu J, Lang HY, O Xiao PG. ‘The occurrence of paeoniflorins and paeonols in Paeniacae’. Yao O See also Jian Zaiyou, Wang Wenquan, Xu Guifang, Xue Xue Bao. 1985 Mar; 20(3):229-34.

OH Meng Li, Hou Junling. ‘Comprehensive quality evaluation of Chi shao by HPLC’. Nutr Hosp. 2013; 28(5):1681-1687 CH3 OH

OH

OH

H

O O

17

O

CH3

PEONY – A Reference for Patients and Professionals

However, this formula usually contains Paeonia lactiflora but versions of it contain Paeonia suffruticosa or sometimes both. The formula with P. lactiflora on its own would obviously not contain as much paeonol as those with P. suffruticosa and so some confusion ensued in the early analytical work on this formula.

It is never a good idea to just concentrate on one chemical from a herb as this can lead to the belief that the whole action of a herb can be ascribed to just one chemical. In fact, the modern process of “standardisation” of a herbal remedy revolves around producing herbal extracts with known quantities of specific chemicals. This process may actually lead to producing a herbal extract that contains measured quantities of one or two chemicals and then very little else besides. This is not a herbal remedy of course, but something more akin to a drug. We also live in a reductionist age in which we try to reduce everything to its component parts. Herbal medicine, on the contrary, is about synergy, the combined action of whole herbs, and those herbs, more often than not, being combined with others. Herbal medicine is about building up not breaking down!

Having said that, herbs are God’s chemical factories and as such produce some outstandingly useful and active chemicals. The peony family of plants is no exception, and has provided some highly effective chemicals for study. Perhaps the most important of these chemicals in Paeonia lactiflora is paeoniflorin.

O H C

CO CH2

O O

CH2OH H

O H OH

H

H

OH

O

H

OH

CH3

OH

Fig. 3. The chemical structure of Paeoniflorin

Paeoniflorin (C23H28O11) is so well studied as an isolated chemical that there is now well over 400 scientific research papers regarding its isolation, structure and activity. Chemically, it is classified as a monoterpene and it has an unusual “cage-like” structure. It is found in Paeonia lactiflora at levels between 0.05% – 5.8% and is highest in year old plants. The Chinese Pharmacopoeia of 2005 stipulates that peony should contain no less than 1.8%. Just like paeonol it has been shown that paeoniflorin exhibits several 18

PEONY – A Reference for Patients and Professionals

interesting effects including being anti-inflammatory, anti-coagulant, anti-hyperglycaemic, anti-arthritic, anti-allergic, anti-depressant and anticonvulsant. Quite an impressive list already, but it also has been shown to improve memory and learning, protect the liver, relax the womb and lower body temperature. Another of its most interesting actions is that it reduces testosterone/androgen production by the ovaries...and more of that later.

An extremely interesting aspect of the medicinal use of peony is that it is commonly used in herbal medicine, and indeed in clinical trials, combined with liquorice. This ‘dynamic duo’, known as “shaoyao gancao tang” in Chinese and “shakuyaku kanzo-to” in Japanese, is commonly used in the treatment of menstrual disorders as we will see below, and they are also prescribed together (along with other herbs) in the above-mentioned skin formula, for example. For those interested in such details, it is thought that the first real mention and promotion of use of this combination was by an extremely important figure in the history of Traditional Chinese Medicine, Zhang Zhongjing. He lived between 150-219 AD (Han Dynasty) and is regarded as one of the most important, learned and pivotal characters in the development of the medical system of his day. The reason for his importance was that he specialised in the treatment of epidemic, infectious diseases such as typhoid and plague. These conditions could wipe out whole populations of course and so the treatment of them was fundamental to the health and survival of whole civilisations and there was little room in the treatment regimens for mumbo jumbo or ineffective medicines. The most interesting general point here is the connection between the peony/liquorice combination and the treatment of diseases that would invariably include high fever and body temperature as a symptom.

What has been discovered is that paeoniflorin itself is poorly absorbed. It is therefore informative to look at exactly what happens to paeoniflorin when it is taken orally as a medicine and how other factors can affect how it is digested and absorbed. It is informative because it demonstrates how herbal medicines are not just unknown, mystical entities, but well studied and effective medicines. Various researchers have studied the passage through the body of orally administered paeoniflorin and it was in the mid 1980’s that it was determined that paeoniflorin, on passage through the gut, is first converted into its aglycone (meaning that it has glucose removed from it) paeoniflorgenin. Paeoniflorgenin is then acted upon by gut bacteria and this leads to the formation of paeonimetabolin-I and paeonimetabolin-II. The paeonimetabolins are then absorbed and exert some of the medicinal effects of Paeonia5.

5.

Shu YZ et al 1987; Akao T et al 1988; Hattori M et al 1985; Heikal OA 1997

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Paeoniflorgenin can itself be absorbed into the blood stream of course6. It was also shown that pure paeoniflorin is a neutral compound with good water solubility but poor lipid solubility, which would explain the poor absorption of the compound itself when taken orally. Pure paeoniflorin (when injected) is excreted/removed from the body quite rapidly via the urine and faeces with no major metabolism in the liver or lungs7. It is also worth stating that when a decoction of chi shao yao is taken, blood levels of paeonimetabolins are higher than if you take the same quantity of a decoction of bai shao yao8.

This result would, of course, be expected given the different ways the root is prepared in the different forms of P. lactiflora as we described elsewhere.

Research has also shown that the normal bacteria found in the intestines of humans, such as Bacteroides fragilis, have high affinity for paeoniflorin and demonstrate potent ability to act upon/digest the molecule. One research team, that of Abdel-Hafez AA et al 1999, actually incubated pure paeoniflorin with various gut bacteria including Bacteroides fragilis and Lactobacillus brevis and obtained 17 paeonimetabolins. Incidentally, 13 of these paeonimetabolin compounds demonstrated anti-convulsive/ anti-epileptic activity in mice. As an important reminder to herbalists – to optimise absorption of herbal remedies make sure the gut flora of your patients is in a healthy state!

Before moving on, it is extremely important to discuss the metabolism of paeoniflorin when combined with the herb liquorice (Glycyrrhiza glabra or Glycyrrhiza uralensis), as this is such an important therapeutic combination both historically and currently.

It has been repeatedly shown that when peony is combined with liquorice there is a remarkable improvement in paeoniflorin/paeonimetabolin absorption9. It is worth repeating what we are talking about now is a combination that is not a modern discovery but a standard, traditional combination. It is also a combination that has become a normal routine therapy alongside drug combinations in Asia (Japan and China). It has been suggested10 that the improved absorption of the paeonimetabolins when peony is taken alongside liquorice may be due to the fact that the saponins of liquorice (the active components) exert a surfactant (detergent like) effect on the lining of the intestine thus improving the solubility of the paeonimetabolins.

6.

7.

8.

9.

10.

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Hsiu SL et al 2003 Orleans NK et al 2013 Wang CH et al 2008 Orleans NK et al 2013 Chen LC et al 2002

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Herbs are God’s chemical factories and produce some outstandingly useful chemicals.

The peony is no exception.

An interesting angle on this improved absorption is shown in the study of He JX et al 2003. The team involved in this study knew that absorption of paeoniflorin metabolites required active gut bacteria, but they also knew that the combination of peony and liquorice was prescribed alongside powerful antibiotic therapy in the treatment of several conditions such as stomach ulcers/Helicobacter pylori. In this instance the herb combination is given to treat the pain of the ulcers, but it would be useless if the gut bacteria were killed by the antibiotic treatment given at the same time. So, they administered large doses of an amoxicillin/metronidazole (broad spectrum antibiotic/ antimicrobial) to rats whilst also being administered a high dose of peony/ liquorice. Just as we would now expect, when given the two combinations the levels of paeonimetabolins in the blood dropped dramatically, because the gut bacteria were wiped out by the antibiotic combination. However, when the antibiotic is dropped and the peony/liquorice combination continued, then by the third day there is a rebound increase in activity of the gut bacteria (2.8 fold increase) and this activity, together with levels of the paeonimetabolins remained high for the subsequent 6 days before falling back to the normal levels of a control group.

When the antibiotic was dropped and no peony/liquorice given, then a similar rebound effect is noted in the activity of gut bacteria (1.4 fold increase) but it is less than that in the group given the peony/liquorice, and it does not last so long. When peony and liquorice were given alone a similar rebound is again observed but it is less than the rebound that happens when 21

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peony and liquorice are combined. In short, it appears that both peony and liquorice are good nutrient sources for gut bacteria but together they exert a synergistic effect. So, it may be that a combination of effects (surfactant effect and nutrient effect) is responsible for the increased absorption of paeonimetabolins when peony is administered along with liquorice.

For those of you interested in such things, here is a list of other chemicals found in Paeonia lactiflora: 1-O-galloylpedunculagin 1, 2, 3, 4, 6-penta-O-galloylglucose 2-methoxy-5-(E)-propenylphenol-beta-vicianoside (phenolic glycoside) 2-O-benzoylpaeoniflorin albiflorin R2 albiflorin R3 3-O-Galloylpaeoniflorin 4-O-methyl-paeoniflorin isopaeoniflorin 6-O-Galloylalbiflorin 6-O-Benzoylpaeoniflorin 6-O-Galloylpaeoniflorin 4-O-galloylal- biflorin 6-O-beta-D-glucopyranosylalbiflorin (monoterpene glycoside) (stimulatory effect on bone formation in vitro11 13-methylmyristic acid Albiflorin (C23H28O11 – molecular weight = 480.46) Astragalin Benzoic acid Benzoylpaeoniflorin Beta-sitosterol Betulinic acid Calcium Catechin Copper 11. Yen PH et al 2007

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Daucosterol Decagalloyl-glucose Essential oil Eugeniin Gallic acid Gallotannins Galloyl-paeoniflorin (an acylated monoterpene glucoside) Glucogallin Glucose Hederagenin Heptagalloyl-glucose Hexagalloyl-glucose Iron Kaempferol-3-glucoside Kaempferol-3, 7-diglucoside Lactifloric acid Lactiflorin Linoleic acid Magnesium Manganese Meso-inositol Nongalloyl-glucose Nor-paeonilactone (an unusual nor-monoterpene) Octagalloyl-glucose Oleanolic acid Oxypaeoniflorin Peonan SA (neutral polysaccharide) Peonan SB (acidic polysaccharide)

PEONY – A Reference for Patients and Professionals

Peonan PA (acidic polysaccharide; all these polysaccharides have immunologic activity12, reticuloendothelial activating activity) Paeonianins Paeonidin Paeoniflorigenone A-E (ellagitannins) Paeoniflorin (glucoside of a pinane type monoterpene, 0.05 - 5.8%) Paeonifloriquinone Paeonilactones-A-B and C Paeonilactone D (monoterpene) Paeonin Paeonin D (monoterpene glucoside) Paeonisuffrone C (monoterpene)

Paeonol (2-hydroxy-4methoxyacetophenone) Palmitic acid Pedunculagin Pentacosan Pentagalloyl-glucose Potassium Quercetin Quercimeritrin Sodium Sucrose Vicianoside Tannin (Z)-1S, 5R-a-pinen-10-YL-avicianoside Zinc

Compounds found in the flowers of P. lactiflora13: Gallic acid methyl gallate ethyl gallate 1,2,3,6-tetragalloyl-beta-Dglucopyranoside 1,2,3,4,6-pentagalloyl-beta-Dglucopyranoside quercetin-3-O-glucoside-6"gallate kaempferol-3-O-glucoside-6"gallate quercetin‐3‐O‐(6β‐O‐galloyl)‐ glucoside 1,2,3,4,6-trigalloyl‐β‐D‐glucose

quercetin-3‐O‐β‐D‐glucoside kaempferol‐3‐O‐(6β‐O‐ galloyl)‐glucoside isohamnetin-3‐O‐β‐D‐ glucoside Kaempferol kaempferol‐3‐O‐β-D-glucoside kaempferol‐7‐O‐β‐D‐glucoside 1-O-galloyl-beta-D-glucose kaempferol-3, 7-di-O-beta-Dglucoside Paeoniflorin Albiflorin

12. Tomoda M et al 1993 13. Shu XK et al 2014 [A]/[B]

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Peonies have a broad application and are exceptionally safe to use.

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So what have peonies been used to treat?

The peonies are herbs I love and use a lot because they have a broad application and are exceptionally safe. They are also safe to use with almost all drugs.

Paeonia lactiflora (chi shao yao) is my peony of choice and I see it as important in three areas: – menstrual/gynaecological problems – epilepsy14 – inflammatory skin disorders such as eczema.

From an even more traditional position I find peony to be useful where a tonic or restorative action is required as it is very nourishing and supportive.

The conditions that are amenable to treatment with Peonies are as follows: Menopause

Peony helps to reduce the discomfort of hot flushes and the sweats that often accompany them. As we have seen, peony is used traditionally to reduce body temperature, skin flushing and redness regardless of the cause. This action of helping to regulate temperature is most likely due to the herbs action on the central nervous system (see below). Traditionally the peonies are also applied to the headaches, dizziness and blurred vision associated with the menopause.

In other words peony can help to clear that ‘fuzzy head’. Studies also point to the anti-depressant effect of peony, and this factor alone would help lift the gloom of an ongoing and disruptive menopause.

If we just take a quick look at the anti-depressant effect of peony then we discover there are several animal studies pointing to this effect. These studies have used various extracts of peony, whole extracts (often referred to as total glycosides of peony/TGP), water and alcohol extracts and pure paeoniflorin15.

Mao QQ et al 2012 conducted a mini review of all the studies available on the anti-depressant effect of peony and stated that (in animal tests) the antidepressant effect of peony is mediated through a variety of mechanisms 14. Never use any herbs for conditions such as epilepsy without the express permission and knowledge of your doctor or specialist and never use herbs to replace your prescribed medication.

15. Mao QQ et al 2008; Mao QQ et al 2009; Qiu F et al 2013

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including mono-amine-oxidase inhibition, neuro-protection (see below), modulation of the hypothalamic-pituitary stress response pathways, inhibition of oxidative stress and up-regulation of neurotrophins. In fact, there was a US patent lodged in 2010 for an anti-depressant drug consisting of albiflorin.

However, getting back to the menopause itself we have the work of Kato T et al 1992, who showed that the combination of peony and liquorice given to rats that had their ovaries removed, or in other words given an instant menopause, led to an increase in circulating DHEA levels. DHEA is a precursor for oestrogen and therefore the combination helped to counter the sudden loss of oestrogen caused by the removal of the ovaries.

Tanaka K et al 2001 also looked at the effect of the peony/liquorice combination in women who had started getting menopausal symptoms due to taking drugs that can bring on the menopause, drugs for endometriosis for example, that effectively block the pituitary hormones that control the menstrual cycle. They found there was a broad improvement in symptoms such as joint aches, hot flushes etc., although there was no alteration in oestrogen levels (which is perhaps a good thing given other drug treatments etc that a patient could be taking). Another use of the peony/ liquorice combination was tested when Sakamoto S et al 1998 used it on 30 postmenopausal women with fibroids who were suffering heavy bleeding and pain. It was found that there was improvement in the symptoms especially in the women with smaller fibroids. If the combination was given alongside drugs such as Buserelin, as an orthodox fibroid treatment, then even the larger fibroids improved.

Another interesting use of peony, is that it turns up in an old Japanese formula known as “Chujo-to”. Lady Chujo, in the eighth century, devised the formula for the maintenance of female health. It is now available in Japan as an over the counter pharmaceutical product. In 1999 it was reported that Chujo-to was effective in halting osteoporosis, a major problem that can arise at the menopause as oestrogen levels fall. There are sixteen herbs in this formula, among them, both Paeonia lactiflora and Paeonia suffruticosa, as well as Angelica sinensis another well known menstrual/gynaecological herb.

There are a lot of herbs in this formula of course, so is there any evidence that peony itself is useful in this respect?

The work of Tsai HY et al 2008 may shed some light on this. They were interested in the role that background inflammation plays in osteoporosis and how this affects the progress of the condition. We will see more about peony and the effect it has on inflammation below. In the meantime, you should be aware that many conditions will have a “background” element of 26

PEONY – A Reference for Patients and Professionals

inflammation as part of the picture of the condition, even if the condition itself is not overtly inflammatory in nature. The team discovered that paeonol in particular had an anti-inflammatory effect by inhibiting macrophages (white blood cells/immune cells) and specifically inhibited osteoclast differentiation. This effect was due to the action paeonol had on controlling the production of inflammatory mediators (see below).

Osteoclasts (to put it simply) are bone cells that are responsible for breaking down old bone. They are normally in balance with osteoblasts that build new bone. In conditions such as osteoporosis, osteoclast activity dominates. They also found that in animal experiments, paeonol administration inhibited bone loss in animals with no ovaries.

A lot of women, by the time they reach the menopause have already had a lot of surgery, problems consequent on birth or investigations in the pelvic area.

Many are left with adhesions, scarring etc. This may have resulted in a source of constant pain. Peony may well help to lessen these problems picked up through a womans reproductive years and is safe to use long-term.

Dysmenorrhoea (period pains)

I would widen this and say that peonies can be used to treat abdominal pain associated with menstrual/gynaecological problems generally. Therefore, the peonies have a useful place in the treatment of not just period pains but pain that is associated with fibroids, endometriosis and adhesions. It is also interesting that the use of peonies for period pain is not just a Chinese or western herbal use, we also know that the Chumash Indians of California used Paeonia californica for period pains16.

Traditionally, peony is applied particularly to cramping, colic type pains, not just in the abdomen, but the back and other muscles. Peony and liquorice have given excellent results when used together in clinical trials on the treatment of dysmenorrhoea (period pains).

Imai A et al 1996 showed that the peony/liquorice combination may work to alleviate period pain because when they treated endometrial cells with the combination they discovered that prostaglandin levels in the cells fell by by 50% as it stimulated the conversion of free arachidonic acid to inert phospholipids. Normally, arachidonic acid can be converted into proinflammatory chemicals that can promote period pain and womb cramps.

This was backed up by Shibata T et al 1996 who demonstrated that when 16. Adams JD et al 2006

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endometrial cells were incubated with peony, liquorice or glycyrrhetinic acid (a component of liquorice) the activity of phospholipase17 was inhibited dose dependently by all three!

Interestingly, peony crops up in other traditional Chinese formulas for period pains, such as in a study conducted on 110 fibroid patients treated with a combination of Peony (bai shao yao), Paeonia suffruticosa, Poria cocos, Prunus persica and Cinnamomum cassia. All the women were under menopausal age. Clinical symptoms improved in 90% of cases and the fibroids shrunk in 60% of cases18.

To change focus slightly for a moment, it is worth pointing out that menstrual cramp is not the only kind of muscle cramp that peony is used to treat. For example, Hinoshita F (2003) showed that at a dosage of 6g a day, peony was effective at reducing the cramps that occur commonly in patients undergoing renal dialysis. Hyodo T et al 2006 further demonstrated that the combination of peony/liquorice when given to 61 dialysis patients, had an “immediate” effect in reducing the muscle cramps. 54 out of the 61 improved. Another interesting aspect of the antispasmodic/anti-cramp effect of the combination of peony and liquorice is found in the study of Ai M et al 2006. They used the peony/liquorice combination as a spray to apply directly to areas of the bowel in 100 patients undergoing colonoscopy.

Relaxation of areas of bowel spasm began within a minute of application of the spray and lasted for 3 minutes. The combination acted on acetylcholine induced spasm and was therefore suggested as a useful antispasmodic agent when anticholinergic drugs such as atropine could not be used. The effect on the bowel muscle was similar to that of peppermint oil. This effect was confirmed by Sakai Y et al 2009 when they took 50 patients with duodenal spasm and sprayed the duodenum with the peony/liquorice combination.

38 of the patients experienced improvement and the combination began working in 50-182 seconds and the effect lasted between 7-21 minutes.

PMS (pre menstrual syndrome)

Peonies are useful in the treatment of irritability, anxiety and the outright aggression that often accompanies PMS. Peony has a mildly tranquillising effect and thus helps the psychological component.

17. Phospholipase is an enzyme that leads to the release of arachidonic acid which may then go on to stimulate inflammation etc.

18. Sakamoto S et al 1992

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Menorrhagia (heavy periods)

Peonies are perfect in the treatment of heavy periods as not only do they help to reduce excess bleeding but traditionally they are used to treat the underlying causes such as fibroids and endometriosis (as discussed elsewhere).

Polycystic ovarian disease/PCOS

This is an increasingly common condition with no known cause. It is characterised by irregular or absent menstruation, weight gain and hirsutism (excess hair growth). It usually starts at puberty. One of the problems with PCOS is that there is a high androgen (male hormone/testosterone) level.

There may or may not be cystic ovaries and the symptoms and hormonal picture can vary greatly from patient to patient.

Some research has pointed to the fact that some of the components of peony root have exhibited anti-androgenic activity. Washida K et al 2009 for example, grew and processed peony in Nara Prefecture, Japan. They isolated the following compounds: 1. 3-O-galloylpaeoniflorin 2. 6-O-galloylalbiflorin 3. Pentagalloylglucose 4. 6-O-benzoylpaeoniflorin 5. 6-O-galloylpaeoniflorin Compounds 2 and 3 were shown to have strong androgen receptor binding capacity. 1., 4., and 5 were weak androgen receptor binders and paeoniflorin and albiflorin, even though related structure-wise are not overt or strong androgen receptor binders, only binding minimally to androgen and oestrogen receptors19. All the compounds were shown to inhibit the growth of androgen dependent prostate cancer cells and so the researchers proposed these compounds as safe, natural anti-androgens.

This activity is interesting from the point of view that androgen receptor antagonist drugs such as Flutamide have been used to treat the androgenic symptoms of PCOS. Be aware though that this situation is not as simple as it may look, but the actions of these compounds on the androgen receptors of women with PCOS may well back up the effects discussed below.

PCOS is one condition where the combination of peony and liquorice has been shown to be highly effective. There are a whole series of Japanese 19. Tamaya T et al 1986

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studies on this combination and its effects on PCOS patients. In Japan the combination of peony and liquorice is called “Shakuyaku-kanzoto�.

In 1982 for example, Yaginuma T et al administered 5-10 grams daily of the combination for 2-8 weeks to 8 infertile women with irregular periods and high testosterone (androgen) levels. Six of them began ovulating regularly, two conceived and seven of them had lowered testosterone levels.

Takahashi K et al 1988, took 20 infertile PCOS patients and gave them the peony/liquorice combination. They also divided the patient group into two.

One group was classified as having a general cystic pattern of PCOS and the other group was classified as having a peripheral cystic pattern of PCOS. In 18 out of the 20 patients plasma testosterone/androgen was lowered and five out of twenty became pregnant. There were slight differences between the two patterns of PCOS and they proposed that the effectiveness of the herbal combination depended on the particular pattern a patient was suffering.

In 1988 Takeuchi T et al carried out a study to deduce how the combination worked on PCOS. They found that (in rats) the combination works on testosterone produced by the ovaries rather than the adrenals and that the testosterone/androgen reduction is dose dependent. Takeuchi T et al 1989, further tested the effect of the peony/liquorice combination, peony by itself and liquorice by itself in androgen sterilised rats. All herbs lowered testosterone/ androgen levels dose dependently whilst the oestradiol-oestrogen/testosterone ratio was elevated. In rats that had their ovaries removed there were no changes in testosterone/androgen or LH/FSH levels. They deduced therefore that the herbs were working in the ovary to stimulate aromatase activity and thus reduce testosterone/androgen levels.

Aromatase is an enzyme that breaks down testosterone/androgen to estrogen. Takeuchi T et al 1991, also incubated ovarian tissue with paeoniflorin, glycyrrhetinic acid and glycyrrhizin. All three significantly lowered testosterone production. The testosterone/delta-4 androstenedione (a precursor of testosterone and oestrogen) production ratio also significantly lowered. The oestradiol-oestrogen/testosterone ratio was significantly increased by glycyrrhetinic acid but not changed by paeoniflorin or glycyrrhizin. Incidentally, glycyrrhizin, a component of liquorice is converted almost completely to glycyrrhetinic acid by gut bacteria20.

A study in 1994 by Takahashi K et al specifically examined the effect of a combination of Paeonia lactiflora and liquorice on polycystic ovarian syndrome (PCOS) sufferers. 34 Japanese women with PCOS were given 20. Takeda S et al 1996

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7.5 grams daily of the combination for 24 weeks. Results showed that testosterone/androgen levels were much decreased, some of the patients became pregnant and the LH to FSH ratio had become closer to the ratio in normal, healthy women. LH and FSH are hormones produced by the pituitary gland in the brain and basically govern the whole menstrual cycle.

In PCOS the levels of these hormones can be well out of balance and thus give rise to several of the symptoms reported by PCOS patients. After 4 weeks treatment, levels of DOPAC and DOPEG were altered significantly, and as these chemicals are metabolites of the neurotransmitters such as dopamine it was thought that this was how the LH/FSH levels were adjusted.

The output of LH and FSH are controlled by the brain of course, as the pituitary gland itself is part of the brain, and it is the neurotransmitters such as dopamine that ultimately control hormone release by the pituitary and thereafter the function of the glands such as the ovaries etc. After 4 weeks on the combination the oestradiol-oestrogen/testosterone ratio was also increased. It is therefore postulated that the peony/liquorice combination exerts its effects by acting directly on the ovaries to stimulate aromatase activity, which reduces testosterone/androgen levels and increases oestrogen/ oestradiol, and that the combination may also have an effect in balancing the FSH/LH levels by acting on neurotransmitters. It is also important to note that the combination does not affect adrenal androgen production or have any effect on testosterone/androgen clearance.

There is an interesting additional finding that we can tag onto the above mentioned effect on LH/FSH levels and the effect that the combination has on the pituitary/neurotransmitters. When people are treated for schizophrenia for example, they are given drugs broadly classified as neuroleptics, also known as anti-psychotics or major tranquilisers including chlorpromazine, risperidone and sertindole. One of the major side-effects of these drugs, because they alter neurotransmitter levels, is that they increase the production of prolactin by the pituitary gland.

This hormone is renowned for its depressant effect, particularly on sexual function and sex-drive. It has been demonstrated that the peony/liquorice combination significantly reduces high prolactin in patients treated with neuroleptics (after 4 weeks) without interfering with the illness or treatment, and the combination may therefore provide a remedy for the loss of sexdrive experienced by such patients21.

21. Yamada K et al 1996

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Post natal PROBLEMS

Some of the earliest European references we have to the use of peonies is that they ‘cleanse the womb’ after birth. Peonies basically help to reduce any post birth bleeding and traditionally are used as an aid in building up new blood.

Peony also helps to fight the depression that can occur after giving birth and is safe if you breast feed.

EpilepsY

We have already seen how the reputation of peony as an anti-epileptic is centuries old. In the UK, as far back as the seventeenth century this effect of peonies was noted. One doctor, John Hall (also the son-in-law of William Shakespeare), became famous for his treatment of epilepsy, thanks to peonies22.

Once again, in the case of peony and epilepsy, we have an example of tradition leading science. We have already noted the work of Abdel-Hafez et al 1999 above and their production of the anti-convulsive paeonimetabolins.

Sugaya A et al 1991, tried to discover how peony worked on epilepsy and which components were active. They prepared various extracts of peony root: a cold water extract, a water and acetone extract, a methanol extract, paeoniflorin, albiflorin and pentagalloylglucose. This is interesting for herbalists because some of these extracts are the type used in general herbal medicine. The extracts were given to rats that had seizures induced chemically. They found that all extracts were effective but the water extract (in effect, a tea!), albiflorin and pentagalloylglucose, when given orally, completely inhibited the EEG changes associated with epilepsy along with the changes of cellular calcium and potassium concentrations that are associated with epilepsy. A nervous impulse is created by the movement of elements such as calcium, sodium and potassium across cell membranes.

Therefore, keeping these levels stable helps damp down random impulses as seen in epilepsy. Sugaya E et al 2006, observed that in induced epilepsy models in rodents that administration of peony root extract led to clear inhibitory effects on electrical bursts in the cerebral cortex. They deduced this effect operated through the medium of the calcium and potassium induced electrical current process again.

The team of Tsuda T et al 1997 had also demonstrated anti-convulsive activity of peony extracts. They showed that continuous administration of peony and its components in an induced epilepsy model led to protection of the cells in the hippocampus area of the brain, preventing cell death. Interestingly, 22. Betts T, Betts H 1998

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Peonies may have a place in the treatment of Alzheimer’s Diesease and other types of agerelated dementia.

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they found that paeoniflorin by itself did not offer complete protection.

Gallotannin by itself also gave incomplete protection. Paeoniflorin and gallotannin together however gave complete protection, which seems to me to be a good case for the use of whole herb rather than isolated components.

Sunaga K et al 2004, also demonstrated in induced epilepsy models in rodents that the long term administration of peony root extract (30 days) led to an increased expression of a gene (A20) that inhibits cell death and thus protected brain cells during convulsions. Kajiwara K et al 2008, also discovered that peony root extract prevented nerve cell death in an induced epilepsy model by promoting the formation of intra-cellular proteins and enhancing glycolysis. This activity was thought to be mediated by interaction with thyroid hormone and retinoid function.

Hino H et al 2012, carried out trials on peony that were set up to mimic febrile convulsions and so cast an interesting light on the effect of peony in terms of its traditional “heat reducing” effect as well as its anti-epileptic effect. They used a traditional formula containing peony (it also contained cinnamon, Zizyphus, liquorice and ginger) and pure paeoniflorin for the tests.

Using a hyperthermia induced epilepsy model in immature rodents they were able to demonstrate a significant suppression of seizures. Paeoniflorin itself was shown to protect cells in the hippocampus by adjusting calcium and glutamate levels in the brain cells. The researchers therefore suggested that peony/paeoniflorin/traditional formulas containing peony would be candidates for the treatment of febrile convulsions in children.

It is interesting to note from the above that peony extracts have the ability to protect brain cells from damage. To fill out this picture a little, paeoniflorin is recently getting attention as it appears to improve cognitive ability, i.e. it aids learning and memory! Peony may therefore have a place in the treatment of Alzheimer’s disease and other types of age related dementia. A lot of the work on this aspect of the activity of peony has been carried out by Japanese research teams. For example, Ohta H et al 1993 [A], discovered that peony root extract significantly prevented scopolamine induced memory impairment in rats. They also found Angelica sinensis to be useful in this respect too!

The same team (Ohta H et al 1993 [B] and [B2]), also demonstrated that pure paeoniflorin reduced scopolamine induced memory deficit in rodents. They found that prazosin significantly blocked this effect whereas yohimbine did not. This suggested that the alpha-1- adrenergic system is involved in the action of paeoniflorin as opposed to the alpha-2-adrenergic system. They also showed that the beta-1-adrenergic systems are involved in the antagonising 34

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effect paeoniflorin has on scopolamine induced cognitive impairment.

On top of showing that daily administration of paeoniflorin improves the learning ability of aged rats, Ohta H et al 1994 [A]/[B], demonstrated that daily administration of paeoniflorin to rodents with lesions of the nucleus basalis magnocellularis has led to improving their learning deficits. The nucleus basalis magnocellularis is important because it can be affected by conditions such as Alzheimer’s disease for example and is thought to be important in learning.

Tabata k et al 2001, found that in rodents, paeoniflorin acted on the adenosine receptor, and specifically, in the hippocampus to enhance cognition. It was also suggested that interaction with this receptor led to acetylcholine release by the cerebral cortex and cells of the hippocampus. The hippocampus is part of the limbic system in the brain and is concerned with consolidating memory.

It is often one of the first areas to suffer in conditions such as Alzheimer’s.

Acetylcholine is a major neurotransmitter in the brain and again is often reduced by degenerative conditions of the brain and nervous system. Liu DZ et al 2005, also deduced that paeoniflorin was operating via the adenosine A1 receptor when they observed a dose dependent reduction in neurological impairment in rats subjected to cerebral ischaemia (stroke).This team actually suggested that paeoniflorin be taken seriously as an anti-stroke drug as, apart from anything else, it was way safer than all others available.

Maintaining the structural integrity and functioning of brain cells is crucial in the treatment of several conditions of course and Liu HQ et al 2006 studied the effect of paeoniflorin in the mouse model of Parkinson’s disease. They found that subcutaneous injection of paeoniflorin led to protection of the dopamine producing cells and that inflammation in these cells was reduced.

They again deduced that this activity was mediated by the interaction of paeoniflorin with the adenosine A1 receptor.

More directly, in terms of protecting brain cells, is the work of Wang D et al 2013 [A]/[B]. They exposed brain cells to a neurotoxin after administration of paeoniflorin and found that the cells were significantly protected by the paeoniflorin treatment. The paeoniflorin treatment led to less damage occurring in the mitochondria and nucleii of the cells under test. They recommended that paeoniflorin be considered as a treatment for neurodegenerative disorders and brain damage. The same team further compared the effects of paeoniflorin and albiflorin on glutamate induced cell death. Once again they found both albiflorin and paeoniflorin offered significant protection to cell cultures exposed to toxins. Interestingly, they also found that there was a slight difference in the actions of albiflorin and 35

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paeoniflorin. Paeoniflorin treated cells did not overload on calcium but the albiflorin cells did not show this, even though they both protected cells.

Again, this may be an example of herb component synergy.

More crude, but very informative is the study of Kim SH et al 2009 in which they exposed brain cell cultures to hydrogen peroxide (bleach)! They discovered that paeonilactone-C and benzoylpaeoniflorin in particular conferred significant protection to the cells exposed to the hydrogen peroxide.

Inflammation is a fundamental part of many conditions including those in the brain and nervous system. Nam KN et al 2013 specifically tested the effect of paeoniflorin in brain tissue and the effect on microglial cells in particular. The microglial cells, to put it simply, are the white blood cells or the immune cells of the nervous system and they are responsible for releasing cytokines that are pivotal in the process of inflammation. Some of these cytokines are responsible for increasing the inflammatory reaction and therefore potentially lead to more damage. The administration of paeoniflorin significantly blocked lipopolysaccharide induced cell death in hippocampal cells and inflammatory cytokine release from microglial cells was reduced.

Cytokines and chemokines are chemicals released by cells such as those of the immune system, involved in an inflammation, and their function is to boost the inflammatory reaction, damp it down or communicate with other cells. (More on cytokines below).

PEONY AS AN ANTI-INFLAMMATORY

In the previous section on epilepsy we touched upon the fact that peony and its constituents exert an anti-inflammatory effect in brain tissue23. Backing this up are a number of studies on peony and its effects on inflammation in various other tissues. We also mentioned elsewhere that in many conditions an underlying inflammation occurs as a background element to those conditions.

In this section we will look at the more general anti-inflammatory effect of peony and in so doing we discover a major benefit of peony and how it may actually be useful in the treatment of a whole host of conditions that may not at first seem an obvious area for the application of this herb.

Prieto JM et al 2003, for example, demonstrated that peony extract inhibited one of the steps in the production of cyclo-oxygenase (COX), an enzyme that is one of the fundamental molecules in promoting inflammation anywhere in the body. Interestingly, they also found the herb Forsythia suspensa to 23. Nam KN et al 2013

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have a similar anti-inflammatory effect, a herb often used along with peony, in inflammatory skin diseases for example.

Lee SJ et al 2003, also found that several components of peony are antiinflammatory with actions including the inhibition of COX-2 and inducible nitric oxide synthase (iNOS). They found that 1, 2, 3, 4, 6-penta-Ogalloyl-beta-D-glucose was the most effective component in inhibiting lipopolysaccharide induced inflammation in cell cultures.

Several studies have demonstrated a potentially useful role for peony in the treatment of inflammatory forms of arthritis such as rheumatoid arthritis and other auto-immune diseases such as SLE (systemic lupus erythematosus).

Zheng YQ et al 2007, tested the effect of orally administered paeoniflorin on rats with induced arthritis. Paeoniflorin reduced the inflammation and reduced synoviocyte proliferation. Various cytokines and chemokines specifically in the synovium (the lining of joints and the primary tissue involved in RA), such as COX-2 were much reduced. Zhang LL et al 2008, also demonstrated that paeoniflorin had an anti-inflammatory effect in induced arthritis models in rodents. Paeoniflorin administration led to reduced synovial inflammation and the reduction of various cytokines and chemokines such as IL-2 (interleukin-2), TNF-a (tumour necrosis factor) and PGE2 (prostaglandin E-2). They also discovered that paeoniflorin altered expression of G-protein. G-proteins, to put it simply, are like molecular switches involved in turning processes such as inflammation on or off. This effect on G-protein was backed up by Chen JY et al 2012. Chang Y et al 2009, further demonstrated that a whole extract of peony root rather than pure paeoniflorin also exerted a positive influence on induced arthritis models in rodents. Peony extract significantly inhibited the proliferation of synoviocytes and decreased levels of IL-1, TNF-a and PGE2. Jiang D et al 2011, specifically used “bai shao yao” against the induced arthritis model in rodents and found the anti-inflammatory effect related to a significant inhibition of cAMP-PDE activity, and that this activity was mediated most powerfully by gallic acid.

As we can see, the anti-inflammatory effect works by affecting a range of different parameters involved in the process of inflammation and other research casts an even wider net over the anti-inflammatory effects of peony and how they are mediated. For example, Zhou Z et al 2012 studied the effect of peony extract on dendritic cells. Dendritic cells are known as antigen presenting cells and are pivotal in stimulating both an immune and inflammatory reaction within the body in response to invading organisms or damage. Because dendritic cells have this role in “turning on” an immune reaction they play a crucial role in the so called auto-immune diseases, 37

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conditions in which the body attacks its own tissues. Dendritic cells are also important in other immune related conditions such as allergy. Examples of auto-immunity include rheumatoid arthritis and SLE. What was discovered was that peony extract decreased the antigen presenting capacity of dendritic cells and as a consequence led to a decrease in T-cell (specific white blood cells or immune cells) proliferation. The researchers suggested that extract of peony may prove to be a valuable treatment for auto-immune conditions.

Lin J et al 2012, took this a little further and used extract of peony in an induced arthritis model in rodents. They discovered that administration of peony extract led to an inhibition of dendritic cells which led to Th1 and Th17 (specific varieties of T-cell) cells being reduced. On top of this they noted a reduction in the production of IL-12 and IL-6. Again, we can see there are many ways in which peony exerts its anti-inflammatory effect and several components of the root combine to produce this effect.

As Zhang W et al 2012 observed, preclinical studies on peony show that peony extract (water and ethanol specifically) reduces pain (note, we have mentioned the use of peony for pain above, in terms of menstrual pain and the pain of ulcers), swelling and synovial hypertrophy in RA and acts by a variety of mechanisms including modulating various cytokines and chemokines and by inhibiting proliferation of lymphocytes (white blood cells/immune cells) and cells of the synovium.

Nowadays it is common to encounter RA patients taking drugs such as methotrexate which is a seriously toxic substance. Basically methotrexate is an anti-cancer drug, it is designed to kill cells. To put it as simply as possible, it is used to treat RA because it kills off your white blood cells and therefore reduces the auto-immune reaction underlying the disease. It’s the medical equivalent of using nuclear weapons to rid your lawn of moles! As you can probably guess methotrexate will also kill your liver if taken for long enough.

Chen Z et al 2013, studied the effect of peony extract on the liver function of 204 patients with RA who were taking methotrexate and leflunomide (another immune suppressing drug). The patients were given the peony extract for 24 weeks.

It was observed that, compared to patients taking just the drugs, there was a significant reduction in the incidence of liver toxicity in the peony group, and more patients in the peony group scored better on a European RA measurement index. Incidentally, it had been previously demonstrated that RA patients given a combination of methotrexate and peony extract actually demonstrated better clinical efficacy and fewer side-effects24.

24. Du JH et al 2005; Wang Y et al 2007

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To return to a previous theme for a second, I want to add that liquorice is also used by herbalists in the treatment of arthritis. It seems peony and liquorice were born to be together!

At this point it is worth looking a little closer at one or two of the autoimmune conditions that peony may be used to treat. As herbalists we do tend to see patients with the more unusual or difficult to treat conditions as modern medicine still has few really effective answers for them and so the patients frequently seek alternative help. SLE, psoriatic arthritis and Sjogren’s Syndrome are auto-immune conditions that are broadly classified along with diseases such as RA. Zhang HF et al 2011 studied the effect of the extract of peony on SLE patients, and was also interested to see if there were any side effects or problems in doing so. They looked at two groups of patients, one group of 29 having taken peony for 5 years or more and another group having taken peony for a year or more but not more than five years. They used the SLE Disease Activity Index to measure results. This index is a list of over 20 features of SLE, including signs and symptoms such as fever, facial rash, alopecia, kidney function measurements etc, and provides a comprehensive scale of severity of the disease. They found that both groups of patients taking the peony were improved compared to controls and most were able to reduce their dosage of prednisolone and cyclophosphamide.

Zhao M et al 2012 [A]/[B], discovered that peony extract stimulated the induction of Treg cells. These cells are cells of the immune system and are involved in damping down immune reactions thus demonstrating another mechanism whereby the peony extract could be acting. In terms of side effects and adverse reactions, there was nothing serious and only a few patients with mild, transient gut upsets and only one or two dropping out of the trials. Wang YN et al 2014, studied the beneficial effect of the extract of peony on 19 patients with psoriatic arthritis. They found that 6 patients exhibited a significant reduction in their symptoms as measured by a disease rating scale and again they concluded that the action of peony was mediated through T cell activity.

Another interesting study on the anti-inflammatory effect of peony and one that, in a way, demonstrates how herbal components synergise and work together, is that of Wang QS (2014). They compared the effectiveness of paeoniflorin to albiflorin in terms of their anti-inflammatory effect by measuring their effects on PGE2, iNOS, IL-6, TNF-a, and COX-2. They discovered that the effects of both chemicals were similar in exerting an anti-inflammatory effect and they recommended that the Chinese Pharmacopoeia be updated by this work.

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Before moving on from the effect of peony on joint inflammation we must mention the fact that peony appears to be useful in reducing the side effects of cancer chemotherapy. Once again, it is the peony/liquorice combination that is important in this treatment. Fuji K et al 2004, found that in 21 patients with epithelial ovarian cancer taking paclitaxel and carboplatin the joint and muscle pain side effects of this treatment, as well as the peripheral neuropathy, were much reduced if the patients were give 7.5g of the peony liquorice combination for just 8 days. 9 cases, 43% showed a reduction in pain. Yoshida T et al 2009, also showed that 50 patients on chemotherapy, if given the peony/liquorice combination prophylactically, was effective at limiting the intensity and duration of the myalgia and arthralgia (muscle and joint pains) caused by the chemo. There are several other studies backing this up, such as Fujiwara H et al 2000, Yamamoto K et al 2001 and Hasegawa K et al 2002. The beauty of this kind of trial is that it demonstrates how well herbal medicine can work with orthodox medicine...if anyone would pay attention!

An extremely important issue surrounding herbal medicines nowadays is their effect on the liver. Some herbs have been removed from commercial circulation on the flimsy basis that a herb may somehow be connected with a liver problem that arose in a person using that herb. Authorities have often blamed a herb for causing problems when the patient in question may have had several other good reasons for the liver problems! In this light it is interesting to note the work of Kim ID et al 2010 because they caused inflammation in the livers of rats and then administered large doses of pure paeoniflorin. This led to inhibition of liver enzyme rises, the maintenance of antioxidant levels in the liver cells and an overall protection of the cells from the inflammation. We must also be aware that peony is often found in combination with other herbs, such as Astragalus membranaceus, to treat liver disease25.

In terms of the other gut organs, apart from the liver, we have already mentioned above how peony (and liquorice) is used in the treatment of stomach ulcers, which are areas of inflammation of course. Again, however, research has found that peony may well be beneficial in the treatment of colitis (inflammation of the bowel). Bear in mind that liquorice, in its own right, used by itself, is great for treating all types of gut inflammation. Zhang J et al 2014, set out to explore the anticolitis effect of paeoniflorin and how this may work. They induced colitis in rodents and then administered paeoniflorin. Paeoniflorin treatment led to a significant reduction in colitis symptoms and they discovered that TNF-a, COX-2 and other inflammatory mediators had been reduced by the treatment. They repeated this test with similar positive results in human colon 25. Sun WY 2007

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cancer cells. To add to these findings, Zhou Y et al 2010 also demonstrated that in the induced colitis model in rodents, paeoniflorin modulated not only the inflammatory mediators but it up-regulated the expression of chemicals known as “defensins” in the gut lining.

Talk about the defensins leads us nicely into discussing the anti-inflammatory effect peony has on the lungs and other areas of the respiratory system. Gan Y et al 2014, demonstrated that paeoniflorin led to up-regulation of defensins in human bronchial epithelial cells. Peony is often used traditionally for respiratory infections and colds etc, and there are studies on its ability to fight the influenza virus26. Now, the most interesting aspect of this trial is that it points out a treatment methodology much loved by herbalists. The methodology in question is that of “strengthening the portals of entry”.

What is this exactly? Well, if you look at the body, there are several areas by which invading organisms can get into the body. The gut would be one such “portal of entry”, as would the lungs. Lining the gut and lungs is a very delicate membrane which is impregnated with immune cells and, as we have just seen, chemical defenses such as defensins. A great example of a herb used traditionally to strengthen the lining of the gut and lungs is Golden Seal (Hydrastis canadensis), but here we have actual research demonstrating that peony may also be a most useful herb to strengthen our natural barriers to invasion by bugs!

It has also been shown that paeoniflorin leads to a reduction of inflammation in the lung tissue of mice and that this worked by down– regulating the inflammatory cytokines such as IL-1beta, TNF-a27. It was also demonstrated by Leem K et al 2004 that peony extract reduced levels of proteins called monocyte chemoattractant proteins (MCP) by human nasal fibroblast cells. MCP’s are potent attraction factors for monocytes which are the largest white blood cells of the immune system. When they get attracted to an area they can do some serious damage, and they are involved in allergic reactions in such places as the nasal membranes, so peony demonstrates potential for the treatment of nasal and upper respiratory inflammation and allergies as well as being potentially useful for inflammation in lung tissue itself.

In our look at the effect of peony and its components on inflammation I want to take a slightly sideways step right now and highlight a surprising area of research. Jiang B et al 2012, was interested in the low grade inflammation that occurs as part of obesity syndrome and how it affects insulin resistance.

A lot has been written about obesity, insulin resistance and “metabolic 26. Ho JY et al 2014 27. Zhou H et al 2011

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syndrome� over the last few years and I do not want to get into it too deeply here. Suffice to say it is associated with central obesity, i.e., lots of fat around the mid-riff and this then is associated with insulin becoming less effective and this leads to problems with sugar and fat metabolism, and the condition becomes a sort of vicious circle with conditions worsening with time, unless there is appropriate intervention. Whilst the condition can stand alone, so to speak, it is also associated most interestingly for us in terms of peony with the menopause and PCOS for example. The inflammation we are talking about in this condition occurs between the fat storage cells of the body, free fatty acids and the macrophages (white blood cells/immune cells).

What Jiang B et al did was to incubate fat cells and macrophages and what they observed was a typical inflammatory response with the macrophages releasing inflammatory cytokines such as TNF-a.

When paeoniflorin was co-incubated with the fat cells and macrophages there was a dose dependant decrease in the amount of inflammatory mediators present. Further to this, Kong P et al 2013 demonstrated that fat cells in the above situation when treated with paeoniflorin had their insulin sensitivity restored and the team suggested that further work was warranted to investigate the use of paeoniflorin in obesity. Whilst this is very interesting in terms of the treatment of obesity itself it does highlight another angle on the way that peony may be helping PCOS patients or menopause patients.

As a final word on inflammation and peony there is an interesting study that was carried out by Jiang WL et al 2009. This study looked at the effect administration of paeoniflorin may have on animals that had systemic inflammation as a result of sepsis. Sepsis means that bacteria for example, circulate freely in the blood stream and the whole body becomes an inflammatory minefield, and it is fatal usually. Administering paeoniflorin in such circumstances led to a dose dependant reduction in a whole array of inflammatory mediators such as TNF-a.

Skin diseases

Even though the effect of peony in terms of the treatment of skin diseases is an anti-inflammatory effect, I have decided to separate this section out as I have found peony such a useful herb in the treatment of skin diseases. My intense interest in this herb developed when, back in the 1990’s, I was honing my own skills in the treatment of childhood eczema, a particularly difficult condition to treat. During this period of time there was a consultant dermatologist, David Atherton, working at Great Ormond St Hospital in London. He noticed that several of his patients had been to see a traditional Chinese herbalist about 42

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their eczema and had experienced significant improvement as a consequence.

He, along with several colleagues researched the Chinese treatments for eczema and discovered there were various formulas used that revolved around using certain herbs. Peony, both P. lactiflora and P. suffruticosa, appeared in these formulas regularly. Dr. Atherton and his colleagues set up trials on these herbs and even went as far as to develop a product from the Chinese herbs, called Zemaphyte, intended for the pharmaceutical market28. The trials were generally positive and my own experience of using these herbs was also extremely positive. However, some trials, it has to be said, were negative, Fung AT et al 1999 for example.

I do not want to dwell too long on this particular set of trials as the formulas included several herbs along with peony, but it was proposed that peony may actually be one of the most important herbs in these formulas, and if nothing else it shows how peony is used in traditional formulas designed to treat inflammatory/hot, red/allergic skin disorders.

It is interesting with regard to the above formulas that there was some confusion initially over the identity of the peony used. Was it P. lactiflora or P. suffruticosa or both (we now know both or one or the other were used)?

This translates chemically, in terms of these herbs active components, into the question, was it paeonol (high in suffruticosa, low in lactiflora) or paeoniflorin (high in lactiflora, low in suffruticosa)...or both? This question was addressed by Lee B et al 2008, when they tested both paeoniflorin and paeonol and the whole root against induced allergic eczema in mice.

They found that all inhibited the allergic reaction but paeoniflorin was most potent at reducing itching/scratching and paeonol was most potent in inhibiting the reaction at cellular level. So, both types of peony would appear to complement each other. More than twenty years before this trial however it had been shown by Yamahara J et al 1982, that paeoniflorin, desbenzoylpaeoniflorin and paeonol inhibited experimental contact hypersensitivity, designed to mimic contact eczema/dermatitis.

Huang J et al 2010, attempted to discern the mechanism of action that paeoniflorin and ginsenoside Rb1 (from Panax spp/ginseng) had on skin inflammation. It was discovered that both reduced levels of several inflammatory cytokines. Chen T et al 2011 specifically tested the effect of paeoniflorin on dermal microvascular, endothelial cells that had been treated with TNF-a.

Under normal circumstances TNF-a, being an inflammatory agent, would lead to the cells starting to express proteins and produce further cytokines to 28. Atherton M et al 1990; Galloway JH et al 1991; Sheehan MP et al [A]/[B]; Sheehan MP et al 1994; Sheehan MP et al 1995; Latchman Y et al 1996; Chan BC et all 2008

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attract white blood cells and perpetuate the inflammation. It is this “rolling” type of inflammation that leads to damage in long term inflammation such as occurs with eczema. When the TNF-a treated cells were also treated with paeoniflorin the chemokine levels were markedly reduced and the researchers suggested that paeoniflorin would be a candidate for treating inflammatory skin diseases.

Wang C et al 2013, attempted to discern the mechanism by which paeoniflorin acts on contact eczema/dermatitis specifically. In mouse models of induced contact dermatitis they found that administration of paeoniflorin led to a significant inhibition of inflammation with an underlying adjustment in the levels of inflammatory cytokines. IL-4 and IL-10, for example, were raised but levels of IL-2 and IL-17 were reduced along with levels of splenocytes and thymocytes (immune cells). The deduction was that paeoniflorin was acting to reduce the inflammation by balancing levels of pro-inflammatory and anti-inflammatory cytokines.

We have already encountered dendritic cells in the process of inflammation and they are also important in the process of skin inflammation and allergy. Shi D et al 2014, found that paeoniflorin inhibited the maturation of dendritic cells in culture and as a consequence reduced their ability to stimulate a T-cell response and consequent inflammatory/allergic reaction.

So, once again we can see that peony and its components exert their effects by affecting various cytokine and chemokine levels and we should see the effect of peony on inflammatory skin diseases in light of the herbs general antiinflammatory effect as well as reflecting upon these more skin biased trials.

Miscellaneous

Peony is used to reduce fevers as well as to treat respiratory infections such as influenza. Studies point to a direct anti-viral effect. Peony has a positive effect on blood lipids and blood flow as well as having a positive influence blood clotting. It is also shown to protect the stomach from ulcer formation.

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A word on combining peonies with other herbs We have already seen that peony is often combined with other herbs, and we have examined the peony/liquorice combination in detail, as well as touching upon the fact peony is combined with Astragalus in liver problems or several other herbs such as Forsythia in the treatment of skin disorders for example. Interestingly, the three peonies we have spoken about are often used together. Worthy of specific mention is the fact that in the treatment of menstrual/gynaecological problems, peony is combined with Rehmannia glutinosa (Chinese foxglove) and Angelica sinensis (Dong Quai) with startling regularity in traditional Chinese formulas.

We saw above how the absorption of paeoniflorin and its metabolites is greatly improved when peony is combined with liquorice. Orleans NK et al 2013 also point out a very interesting finding, in terms of the absorption of paeoniflorin, when peony was combined with Angelica sinensis in animal tests. They showed that this combination actually led to a decrease in the absorption of paeoniflorin and its metabolites! An extremely interesting finding in light of the fact we have just pointed how regularly these two herbs are combined. However, the same team also point out that the absorption of paeoniflorin can be improved if the traditional Chinese formula “Dangguishaoyao- san” is used. This formula is Angelica sinesis and peony together with Atractylodes, Alisma, Poria and Ligusticum.

What you find in traditional Chinese medicine is that peony is typically combined with other herbs from the same categories that the peonies themselves are in and they would be combined in order to assist the effect of peony. This is where the “art” of herbal medicine comes in and where it departs radically from pharmaceutical prescribing. Many of the herbs in the same category as peony are also well known for their menstrual/gynaecological uses, Leonurus heterophyllus (Motherwort) and Rosa chinensis (Chinese tea rose) for example.

Unfortunately, the way herbs are being legislated for in Europe nowadays means that herb combinations are very difficult to bring to market and register, but we must always be aware of this traditional approach by herbalists in the treatment of illness where combinations and synergy are paramount.

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Peony is often combined with other herbs to enhance its effect.

Just to repeat, never forget the value of the peony/liquorice combination.

You should consult your herbalist if you feel you may need to step up your treatment from using peony alone.

Find a herbalist here – www.nimh.org.uk.

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Checklist for the best uses of peony We have just discussed a great deal of information regarding the research on peony and what it may be potentially used to treat. As you can see, there can be a confusing array of potential applications for a given herb. What we need to do though is make use of the herb in the most effective fashion. So, what I now want to do is to “skin” all the information and to make a list of the conditions in which peony would be a “first choice”. Hopefully, this list will be of great benefit to practitioners in their formulating for specific patients.

As I said at the outset, I always see peony best placed in the treatment of menstrual/gynaecological conditions, epilepsy and inflammatory skin conditions. Now I’ll put a bit of meat on these bare bones.

Menstrual/gynaecological conditions – PCOS – (alone or with liquorice) – Menopausal symptoms – Dysmenorrhoea (period pains) – (both primary, i.e. without underlying gynaecological conditions, and for the conditions such as fibroids, endometriosis etc that can lead to dysmenorrhoea).

Epilepsy All types of epilepsy. (Note: Even though it may be recommended not to combine orthodox drugs such as phenytoin with peony, there is actually no direct interaction or known danger in doing so).

Remember, never use any medicine or adjust your treatment for epilepsy without seeking the advice of your health care practiotioner.

Inflammatory skin disorders: – Atopic eczema/dermatitis – Contact dermatitis – Psoriasis Arthritis: – Rheumatoid arthritis – Sero negative arthropathies such as SLE, Sjogren’s and psoriatic arthropathy – As an adjuvant in patients on methotrexate type drugs 47

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Peony represents another important treatment option for the modern era

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What is the dosage of the peonies?

Traditional dosage for peony, which would be a tea made from the dried herb, is 2-6g daily.

Obviously, when you purchase a prepared tablet, capsule or tincture of peony then you should stick to the recommended dosage on the label.

Also look out for the product having a THR number which is a Traditional Herbal Registration number as this means the product has gone through an extremely expensive and lengthy pharmaceutical type quality control and manufacturing process demanded by European legislation for herbal medicines.

Are there any side-effects of peony?

Can I take it with other medicines?

One of the most important aspects of the activity of peony and something that makes it one of the most versatile and useful herbs is the fact that even though it is used to treat menstrual and gynaecological conditions, it does not rely for its actions on influencing or acting upon oestrogen or hormone receptors. Thanks to this, peony can safely be used with hormonal medication such as HRT or Tamoxifen. Some herbs, such as Red clover, work by directly interacting with oestrogen/female hormone receptor sites and this means herbs like this can not be used if other hormonal medication is being used.

Herbs such as Red clover are referred to as the phytooestrogenic herbs. Peony therefore represents another important treatment option for the modern era when we are awash with oestrogenic and hormonal drugs. Peony could of course be used along-side phyto-oestrogenic herbs, thus attacking a problem from 2 different angles.

Another important question is if peony can be used with anti-epileptics. It can, even though a standard, modern recommendation is not to.

There are many gynaecological conditions that peony can be used to treat.

Many of these conditions such as fibroids, PCOS and endometriosis can also cause heavy bleeding. Be aware that peony should not be used if the bleeding is actually caused by/or complicated by a blood clotting disorder rather than a primary underlying gynaecological disorder as peony is also a blood thinner.

In summary, peony is a very safe herb and the only reported problems from studies involve indigestion or stomach upsets which resolve when the peony is stopped. The only drugs that peony should be used with caution with are drugs that thin the blood such as warfarin.

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There are herbs in use in the clinics of herbalists that would blow the commercially popular ones out of the water in terms of their actions and effects.

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References Abdel-Hafez AA, Meselhy MR, Nakamura N, Hattori M, Watanabe H, Murakami Y, El-Gendy MA, Mahfouz NM, Mohamed TA. ‘Anticonvulsant activity of paeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis’. Biol Pharm Bull. 1999 May; 22(5):491-7 Adams JD Jr, Garcia C. ‘Women’s health among the Chumash’. Evid Based Complement Alternat Med. 2006 Mar; 3(1):125-31 Akao T, Shu YZ, Matsuda Y, Hattori M, Namba T, Kobashi K. ‘Metabolism of paeoniflorin and related compounds by human intestinal bacteria. IV. Formation and structures of adducts of a metabolic intermediate with sulfhydryl compounds by Lactobacillus brevis’. Chem Pharm Bull (Tokyo). 1988 Aug; 36(8):3043-8 Atherton M, Sheeham M, Rustin HA, Buckley C, Brostoff J, Taylor N. ‘Chinese herbs for eczema’ [Letter]. Lancet 1990; 336: 1254.

Baba S. ‘Isotope effects in the biological processes--isotope effect in the drug metabolism study’. Radioisotopes. 1986 Apr; 35(4):201-5 Betts T, Betts H. ‘John Hall and his epileptic patients - epilepsy management in early 17th century England’. Seizure. 1998 Oct; 7(5):411-4 Brandes R, Roth HJ. ‘The 3 isomeric morpholine-Mannich-bases of paeonol’. Arch Pharm Ber Dtsch Pharm Ges. 1967 Dec; 300(12):1005-7 Cao W, Zhang W, Liu J, Wang Y, Peng X, Lu D, Qi R, Wang Y, and Wang H. ‘Paeoniflorin improves survival in LPS‐challenged mice through the suppression of TNF‐α and IL‐1β release and augmentation of IL‐10 production’.

Int. Immunopharmacol. 2011, 11, 172–178 43 Chan BC, Hon KL, Leung PC, Sam SW, Fung KP, Lee MY, Lau HY. ‘Traditional Chinese medicine for atopic eczema: PentaHerbs formula suppresses inflammatory mediators release from mast cells’. J Ethnopharmacol. 2008; 120:85–91 Chang WS, Chang YH, Lu FJ, Chiang HC. ‘Inhibitory effects of phenolics on xanthine oxidase’. Anticancer Res. 1994 Mar-Apr; 14(2A):501-6.

Chang Y, Wei W, Zhang L, Xu HM. ‘Effects and mechanisms of total glucosides of peony on synoviocytes activities in rat collagen-induced arthritis’.

J Ethnopharmacol. 2009 Jan 12; 121(1):43-8 Chen JY, Wu HX, Chen Y, Zhang LL, Wang QT, Sun WY, Wei W. ‘Paeoniflorin inhibits proliferation of fibroblast-like synoviocytes through suppressing G-protein-coupled receptor kinase 2’. Planta Med. 2012 May; 78(7):665-71

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PEONY – A Reference for Patients and Professionals

Chen LC, Chou MH, Lin MF, Yang LL. ‘Pharmacokinetics of paeoniflorin after oral administration of Shaoyao Gan-chao Tang in mice’. Jpn J Pharmacol. 2002 Mar; 88(3):250-5 Chen T, Guo ZP, Jiao XY, Jia RZ, Zhang YH, Li JY, Huang XL, Liu HJ. ‘Peoniflorin suppresses tumor necrosis factor‐α induced chemokine production in human dermal microvascular endothelial cells by blocking nuclear factor‐κB and ERK pathway’. Arch Dermatol Res. 2011 Jul; 303(5):351-60 Chen Z, Li XP, Li ZJ, Xu L, Li XM. ‘Reduced hepatotoxicity by total glucosides of peony in combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.’ Int Immunopharmacol. 2013 Mar; 15(3):474-7 Ding A, Guo R, Rong J. Determination of paeonol in carbonized bark of Paeonia suffruticosa Andr. by HPLC.Chung Kuo Chung Yao Tsa Chih. 1996 Jan; 21(1):23-4, 63 Du JH, Dong BD. ‘Comparative study on clinical efficacy of using methotrexate singly or combined with total glucosides of Paeony in treating rheumatoid arthritis’. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005 Jun; 25(6):540-2 Feng L, Liu QJ, Sun XW. ‘Quantitative determination of paeonol in nujin pills by gas chromatography’. Chung Kuo Chung Yao Tsa Chih. 1994 Feb; 19(2):92-3, 127 Fujii K, Okamoto S, Saitoh K, Sasaki N, Takano M, Tanaka S, Kudoh K, Kita T, Tode T, Kikuchi Y. ‘The efficacy of Shakuyaku-Kanzo-to for peripheral nerve dysfunction in paclitaxel combination chemotherapy for epithelial ovarian carcinoma’. Gan To Kagaku Ryoho. 2004 Oct; 31(10):1537-40 44 Fujiwara H, Urabe T, Ueda K, Mizunoe T, Date K, Nakano M, Honda N, Sakashita T, Fujito N. ‘Prevention of arthralgia and myalgia from paclitaxel and carboplatin combination chemotherapy with Shakuyaku-kanzoto’.

Gan To Kagaku Ryoho. 2000 Jul; 27(7):1061-4 Fung AY, Look PC, Chong LY, But PP, Wong E. ‘A controlled trial of traditional Chinese herbal medicine in Chinese patients with recalcitrant atopic dermatitis’.

Int J Dermatol. 1999; 38:387–392 Galloway JH, Marsh ID, Bittiner SB, et al. ‘Chinese herbs for eczema, the active compound?’ Lancet 1991; 337: 566.

Galloway JH, Marsh ID, Bittiner SB, Messenger AG, Gawkrodger DJ, Glet R, Forrest AR. ‘Chinese herbs for eczema, the active compound?’ Lancet. 1991 Mar 2; 337(8740):566 Gan Y, Cui X, Ma T, Liu Y, Li A, Huang M. ‘Paeoniflorin Upregulates β‐Defensin‐2 Expression in Human Bronchial Epithelial Cell Through the p38 MAPK, ERK, and NF‐κB Signaling Pathways’. Inflammation. 2014 Apr 4 Gao C, Wu Y, Wang Y, Yan J, Pan H, Cao, L, and Liang R. ‘Anti- Inflammatory and analgesic effects of total glucosides of paeonia injection’. Zhong Yao Xin Yao Yu Lin Chuang Yao Li. 2002, 13, 163–165 Gjertsen FB, Solheim E, Scheline RR. ‘Metabolism of aromatic plant ketones in rats: acetovanillone and paeonol’. Xenobiotica. 1988 Feb;18(2):225-34

52

PEONY – A Reference for Patients and Professionals

Goto H, Shimada Y, Akechi Y, Kohta K, Hattori M, Terasawa K. ‘Endotheliumdependent vasodilator effect of extract prepared from the roots of Paeonia lactiflora on isolated rat aorta’. Planta Med. 1996 Oct; 62(5):436-9 Grebeniuk VN, Mannanov AM, Korsun VF, Vinogradova AI. ‘Peony tincture in the complex treatment of allergic dermatoses’. Vestn Dermatol Venerol. 1987; (10):46-8 Harada M, Suzuki M, Ozaki Y. ‘Effect of Japanese Angelica root and peony root on uterine contraction in the rabbit in situ’. J Pharmacobiodyn. 1984 May; 7(5):304-11 Harada M, Yamashita A, Aburada M. ‘Pharmacological studies on the root bark of Paeonia moutan. II. Antiinflammatory effect, preventive effect on stressinduced gastric erosion, inhibitory effect on gastric juice secretion and other effects of paeonol’. Yakugaku Zasshi. 1972 Jun; 92(6):750-6 45 Harada M, Yamashita A. ‘Pharmacological studies on the root bark of paeonia moutan. I. Central effects of paeonol’. Yakugaku Zasshi. 1969 Sep; 89(9):1205-11 Hasegawa K, Mizutani Y, Kuramoto H, Nagao S, Masuyama H, Hongo A, Kodama J, Yoshinouchi M, Hiramatsu Y, Kudo T, Okuda H. ‘The effect of L-Glutamine and Shakuyaku-Kanzo-to for paclitaxel-induced myalgia/arthralgia’. Gan To Kagaku Ryoho. 2002 Apr; 29(4):569-74 Hattori M, Shu YZ, Shimizu M, Hayashi T, Morita N, Kobashi K, Xu GJ, Namba T. ‘Metabolism of paeoniflorin and related compounds by human intestinal bacteria’. Chem Pharm Bull (Tokyo). 1985 Sep; 33(9):3838-46 He DY, Dai SM. ‘Anti-inflammatory and immunomodulatory effects of Paeonia lactiflora pall., a traditional chinese herbal medicine’. Front Pharmacol. 2011 Feb 25; 2:10 He JX, Akao T, Tani T. ‘Restorative effect of repetitive administration of ShaoyaoGancao-tang on bioavailability of paeoniflorin reduced by antibacterial synthetic drugs treatment in rats’. Biol Pharm Bull. 2003 Nov; 26(11):1585-90 Heikal OA, Akao T, Takeda S, Hattori M. ‘Pharmacokinetic study of paeonimetabolin I, a major metabolite of paeoniflorin from paeony roots.’

Biol Pharm Bull. 1997 May; 20(5):517-21 Hino H, Takahashi H, Suzuki Y, Tanaka J, Ishii E, Fukuda M. ‘Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children’. PLoS One. 2012; 7(8):e42920 Hinoshita F, Ogura Y, Suzuki Y, Hara S, Yamada A, Tanaka N, Yamashita A, Marumo F. ‘Effect of orally administered shao-yao-gan-cao-tang (Shakuyakukanzo-to) on muscle cramps in maintenance hemodialysis patients: a preliminary study’. J Chin Med. 2003; 31(3):445-53 Hirai A, Terano T, Hamazaki T, Sajiki J, Saito H, Tahara K, Tamura Y, Kumagai A. ‘Studies on the mechanism of antiaggregatory effect of Moutan Cortex’. Thromb Res. 1983 Jul 1; 31(1):29-40 Ho JY, Chang HW, Lin CF, Liu CJ, Hsieh CF, Horng JT. ‘Characterization of the anti-influenza activity of the Chinese herbal plant Paeonia lactiflora’. Viruses.

2014 Apr 23; 6(4):1861-75

53

PEONY – A Reference for Patients and Professionals

Hsiu SL, Lin YT, Wen KC, Hou YC, Chao PD. ‘A deglucosylated metabolite of paeoniflorin of the root of Paeonia lactiflora and its pharmacokinetics in rats’.

Planta Med. 2003 Dec; 69(12):1113-8 46 Hu Q, Shi YL. ‘Inhibition of voltage-gated K+, Na+ and Ca2+ currents in neuroblastoma x glioma hybrid cells by paeonol’. Sheng Li Hsueh Pao. 1994 Dec; 46(6):575-80 Huang J, Qiu L, Ding L, Wang S, Wang J, Zhu Q, Song F, Hu J. ‘Ginsenoside Rb1 and paeoniflorin inhibit transient receptor potential vanilloid‐1‐activated IL‐8 and PGE₂ production in a human keratinocyte cell line HaCaT’.

Int Immunopharmacol. 2010 Oct; 10(10):1279-83 Hyodo T, Taira T, Takemura T, Yamamoto S, Tsuchida M, Yoshida K, Uchida T, Sakai T, Hidai H, Baba S. ‘Immediate effect of Shakuyaku-kanzo-to on muscle cramp in hemodialysis patients’. Nephron Clin Pract. 2006; 104(1): c28-32 Imai A, Horibe S, Fuseya S, Iida K, Takagi H, Tamaya T. ‘Possible evidence that the herbal medicine shakuyaku-kanzo-to decreases prostaglandin levels through suppressing arachidonate turnover in endometrium’. J Med. 1995; 26(3-4):163-74 Ishida H, Takamatsu M, Tsuji K, Kosuge T. ‘Studies on active substances in herbs used for oketsu (“stagnant blood”) in Chinese medicine. V. On the anticoagulative principle in moutan cortex’ Chem Pharm Bull (Tokyo). 1987 Feb; 35(2):846-8 Jiang B, Qiao J, Yang Y, Lu Y. ‘Inhibitory effect of paeoniflorin on the inflammatory vicious cycle between adipocytes and macrophages’. J Cell Biochem. 2012 Aug; 113(8):2560-6 Jiang D, Chen Y, Hou X, Xu J, Mu X, Chen W. ‘Influence of Paeonia lactiflora roots extract on cAMPphosphodiesterase activity and related anti-inflammatory action’. J Ethnopharmacol. 2011 Sep 1; 137(1):914-20 Jiang WL, Chen XG, Zhu HB, Gao YB, Tian JW, Fu FH. ‘Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis’. Basic Clin Pharmacol Toxicol. 2009 Jul; 105(1):64-71 Jin CD. ‘Multivariate quantitative correlation analysis of chemical constituents of peony root in different collecting seasons’. Chung Kuo Chung Yao Tsa Chih.

1993 Jun; 18(6):333-4, 380-1 Kajiwara K, Sunaga K, Tsuda T, Sugaya A, Sugaya E, Kimura M. ‘Peony root extract upregulates transthyretin and phosphoglycerate mutase in mouse cobalt focus seizure’. Biochem Biophys Res Commun. 2008 Jul 4; 371(3):375-9 Kato T, Okamoto R. ‘Effect of shakuyaku-kanzo-to on serum estrogen levels and adrenal gland cells in ovariectomized rats’. Nihon Sanka Fujinka Gakkai Zasshi.

1992 Apr; 44(4):433-9 47 Kawashima K, Miwa Y, Kimura M, Mizutani K, Hayashi A, Tanaka O. ‘Diuretic action of paeonol’.Planta Med. 1985 Jun;(3):187-9 Kim ID and Ha BJ. ‘Paeoniflorin protects RAW 264.7 macrophages from LPSinduced cytotox-icity and genotoxicity’. Toxicol In Vitro. 2009, 23, 1014–1019

54

PEONY – A Reference for Patients and Professionals

Kim ID, Ha BJ. ‘The effects of paeoniflorin on LPS-induced liver inflammatory reactions’. Arch Pharm Res. 2010 Jun; 33(6):959-66 Kim SH, Lee MK, Lee KY, Sung SH, Kim J and Kim YC. ‘Chemical constituents isolated from Paeonia lactiflora roots and their neuroprotective activity against oxidative stress in vitro’. J. Enzyme Inhib. Med. Chem. 2009, 24, 1138–1140 Kojima S, Inaba K, Kobayashi S, Kimura M. ‘Inhibitory effects of traditional Chinese medicine Shimotsu-to and its included crude fractions on adjuvantinduced chronic inflammation of mice’. Biol Pharm Bull. 1996 Jan; 19(1): 47-52 Kong P, Chi R, Zhang L, Wang N, Lu Y. ‘Effects of paeoniflorin on tumor necrosis factor‐α‐induced insulin resistance and changes of adipokines in 3T3-L1 adipocytes’. Fitoterapia. 2013 Dec; 91:44-50 Latchman Y, Banerjee P, Poulter LW, Rustin M, Brostoff J. ‘Association of immunological changes with clinical efficacy in atopic eczema patients treated with traditional Chinese herbal therapy (Zemaphyte)’. Int Arch Allergy Immunol 1996; 109: 243-9 Lee B, Shin YW, Bae EA, Han SJ, Kim JS, Kang SS, and Kim DH. ‘Antiallergic effect of the root of Paeonia lactiflora and its constituents paeoniflorin and paeonol.’

Arch. Pharm. Res. 2008, 31, 445–450 Lee SJ, Lee IS, Mar W. ‘Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 activity by 1,2,3,4,6-penta-O-galloyl-beta-D-glucose in murine macrophage cells’. Arch Pharm Res. 2003 Oct; 26(10):832-9 Leem K, Kim H, Boo Y, Lee HS, Kim JS, Yoo YC, Ahn HJ, Park HJ, Seo JC, Kim HK, Jin SY, Park HK, Chung JH, Cho JJ. ‘Effects of Paeonia lactiflora root extracts on the secretions of monocyte chemotactic protein-1 and -3 in human nasal fibroblasts’. Phytother Res. 2004 Mar; 18(3):241-3 48 Li J, Chen M Z, and Xu S Y. ‘Effect of total glucosides of paeony on prostaglandin E2 derived from peritoneal macrophages and related mechanisms in rats’.

Zhongguo Yao Li Xue Tong Bao. 1994, 10, 267– 270 Li J, Zhao W, Chen M, and Xu S. ‘Effect of total glucosides of paeony on leukotriene B4 by perito-neal macrophages in rats’. Zhongguo Yao Li Xue Tong Bao. 1992, 8, 36–39 Li FC, Zhou XL, Mao HL. ‘A study of paeonol injection on immune functions in rats’. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 1994 Jan;14(1):37-8, 6 Li SZ. ‘Method of stewing the cortex of mudan radicis in medical potions’. Chung Yao Tung Pao. 1986 May; 11(5):36-7 Liang JS, Chen M Z, and Xu S Y. ‘Effect of total glucosides of paeony on the function of peritoneal macrophages in rats’. Zhongguo Yao Li Xue Yu Du Li Xue Za Zhi. 1990, 4, 153–154 Liapina LA, Ammosova IaM, Novikov VS, Osipova NN, Smolina TIu, Pastorova VE, Uspenskaia MS, Liapin GIu. ‘The nature of an anticoagulant isolated from peonies in the central zone of Russia’. Izv Akad Nauk Ser Biol. 1997 Mar-Apr; (2):235-7

55

PEONY – A Reference for Patients and Professionals

Liapina LA, Novikov VS, Pastorova VE, Uspenskaia MS, Smolina TIu, Liapin GIu. ‘An anticoagulant from extracts of peony roots: its isolation and properties’. Izv Akad Nauk Ser Biol. 1995 Mar-Apr; (2):249-51 Lin HC, Ding HY, Ko FN, Teng CM, Wu YC. ‘Aggregation inhibitory activity of minor acetophenones from Paeonia species’. Planta Med. 1999 Oct; 65(7):595-9 Lin J, Xiao L, Ouyang G, Shen Y, Huo R, Zhou Z, Sun Y, Zhu X, Zhang J, Shen B, Li N. ‘Total glucosides of paeony inhibits Th1/Th17 cells via decreasing dendritic cells activation in rheumatoid arthritis’. Cell Immunol. 2012 Dec; 280(2):156-63 Liu DZ, Xie KQ, Ji XQ, Ye Y, Jiang CL, Zhu XZ. ‘Neuroprotective effect of paeoniflorin on cerebral ischemic rat by activating adenosine A1 receptor in a manner different from its classical agonists’. Br J Pharmacol. 2005 Oct; 146(4):604-11 Liu HQ, Zhang WY, Luo XT, Ye Y, Zhu XZ. ‘Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease by activation of adenosine A1 receptor’.

Br J Pharmacol. 2006 Jun; 148(3):314-25 49 Maeda T, Shinozuka K, Baba K, Hayashi M, Hayashi E. ‘Effect of shakuyakukanzoh-toh, a prescription composed of shakuyaku (Paeoniae Radix) and kanzoh (Glycyrrhizae Radix) on guinea pig ileum’. J Pharmacobiodyn. 1983 Mar; 6(3):153-60 Mao QQ, Ip SP, Ko KM, Tsai SH, Che CT. ‘Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress: effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor’. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Oct 1; 33(7):1211-6 Mao QQ, Ip SP, Tsai SH, Che CT. ‘Antidepressant-like effect of peony glycosides in mice’. J Ethnopharmacol. 2008 Sep 26; 119(2):272-5 Mao QQ, Ip SP, Xian YF, Hu Z, Che CT. ‘Anti-depressant-like effect of peony: a mini-review’. Pharm Biol. 2012 Jan; 50(1):72-7 Mimura K, Baba S. ‘Determination of paeonol metabolites in man by the use of stable isotopes’. Chem Pharm Bull (Tokyo). 1981 Jul; 29(7):2043-50 Mimura K, Baba S. ‘Studies on the biotransformation of paeonol by isotope tracer techniques. II. Species differences in metabolism’. Chem Pharm Bull (Tokyo).

1980 Jun; 28(6):1704-10 Mimura K, Baba S. ‘Studies on the biotransformation of paeonol by means of isotope tracer techniques. Synthesis and physicochemical properties of carbon-13 and deuterium labeled compounds.’ Radioisotopes. 1979 Dec; 28(12):739-44 Mimura K, Baba S. ‘Studies on the percutaneous absorption of paeonol by using stable isotopes’. Chem Pharm Bull (Tokyo). 1983 Oct; 31(10):3698-706 Mimura K, Baba S. ‘Studies on the percutaneous absorption of paeonol in experimental animals by a radioactive tracer technique’. Radioisotopes. 1983 Jan; 32(1):7-12

56

PEONY – A Reference for Patients and Professionals

Mimura K, Furuta T, Baba S. ‘Kinetic isotope effect on metabolism of deuterated paeonol’. Yakugaku Zasshi. 1982 May; 102(5): 458-62 Nagasawa H, Iwabuchi T, Inatomi H. ‘Protection by tree-peony (Paeonia suffruticosa Andr) of obesity in (SLN x C3H/He) F1 obese mice’. In Vivo. 1991 Mar-Apr; 5(2):115-8 50 Nam KN, Yae CG, Hong JW, Cho DH, Lee JH, Lee EH. ‘Paeoniflorin, a monoterpene glycoside, attenuates lipopolysaccharide-induced neuronal injury and brain microglial inflammatory response’. Biotechnol Lett. 2013 Aug; 35(8):1183-9 Ohta H, Matsumoto K, Shimizu M, Watanabe H. ‘Paeoniflorin attenuates learning impairment of aged rats in operant brightness discrimination task’. Pharmacol Biochem Behav. 1994 Sep; 49(1):213-7. [A] Ohta H, Matsumoto K, Watanabe H, Shimizu M. ‘Involvement of alpha 1- but not alpha 2-adrenergic systems in the antagonizing effect of paeoniflorin on scopolamine-induced deficit in radial maze performance in rats’. Jpn J Pharmacol. 1993 Jun;62(2):199-202. [B] (see also B2) Ohta H, Matsumoto K, Watanabe H, Shimizu M. ‘Involvement of beta-adrenergic systems in the antagonizing effect of paeoniflorin on the scopolamineinduced deficit in radial maze performance in rats’. Jpn J Pharmacol. 1993 Aug; 62(4):345-9. [B2] Ohta H, Ni JW, Matsumoto K, Watanabe H, Shimizu M. ‘Peony and its major constituent, paeoniflorin, improve radial maze performance impaired by scopolamine in rats’. Pharmacol Biochem Behav. 1993 Jul; 45(3):719-23 Ohta H, Ni JW, Matsumoto K, Watanabe H, Shimizu M. ‘Peony and its major constituent, paeoniflorin, improve radial maze performance impaired by scopolamine in rats’. Pharmacol Biochem Behav. 1993 Jul; 45(3):719-23. [A] Ohta H1, Nishi K, Matsumoto K, Shimizu M, Watanabe H. ‘Paeoniflorin improves learning deficit in 4-arm baited radial maze performance in rats with unilateral nucleus basalis magnocellularis lesion’. Phytomedicine. 1994 Sep; 1(2):117-21. [B] Okubo T, Nagai F, Seto T, Satoh K, Ushiyama K, Kano I. ‘The inhibition of phenylhydroquinone-induced oxidative DNA cleavage by constituents of Moutan Cortex and Paeoniae Radix’. Biol Pharm Bull. 2000 Feb; 23(2):199-203 Orleans NK, Martey, Xiaoyan S, Xin H: Advance in pre-clinical pharmacokinetics of paeoniflorin, a major monoterpene glucoside from the root of Paeonia lactiflora. Pharmacology & Pharmacy, 2013, 4, 4-14 Ou-Yang Y. ‘Research of alcohol extract of Paeonia lactiflora Pall in antiinflammatory and analgesic effect’. Shu Li Yi Yao Za Zhi. 2008, 21, 600–602 Pastorova VE, Liapina LA, Uspenskaia MS, Ziadetdinova GA. ‘Effects of the water and ethanol extracts from the root bark of the peony Paeonia lutea on the hemostatic blood parameters’. Biull Eksp Biol Med. 1999 May; 127(5):533-5 51 Prieto JM, Recio MC, Giner RM, Máñez S, Giner-Larza EM, Ríos JL. ‘Influence of traditional Chinese antiinflammatory medicinal plants on leukocyte and platelet functions’. J Pharm Pharmacol. 2003 Sep; 55(9):1275-82

57

PEONY – A Reference for Patients and Professionals

Qiu F, Zhong X, Mao Q, Huang Z.’ The antidepressant-like effects of paeoniflorin in mouse models’. Exp Ther Med. 2013 Apr; 5(4):1113-1116 Riley CM, Ren TC. ‘Simple method for the determination of paeonol in human and rabbit plasma by highperformance liquid chromatography using solid-phase extraction and ultraviolet detection’. J Chromatogr. 1989 Apr 14; 489(2):432-7 Robinson M, MD, The New Family Herbal and Botanic Phyician, W Nicholson & Son, Paternoster Square, London. 1900.

Sakai Y, Nagase H, Ose Y, Kito H, Sato T, Kawai M, Mizuno M. ‘‘Inhibitory action of peony root extract on the mutagenicity of benzo[a]pyrene’. Mutat Res. 1990 Jun; 244(2):129-34 Sakamoto S, Kudo H, Suzuki S, Sassa S, Yoshimura S, Nakayama T, Maemura M, Mitamura T, Qi Z, Liu XD, Yagishita Y, Asai A. ‘Pharmacotherapeutic effects of toki-shakuyaku-san on leukorrhagia in young women’. Am J Chin Med. 1996; 24(2):165-8 Sakamoto S, Mitamura T, Iwasawa M, Kitsunai H, Shindou K, Yagishita Y, Zhou YF, Sassa S. ‘Conservative management for perimenopausal women with uterine leiomyomas using Chinese herbal medicines and synthetic analogs of gonadotropin-releasing hormone’. In Vivo. 1998 May-Jun; 12(3):333-7 Sheehan MP, Atherton DJ.’A controlled trial of traditional Chinese medicinal plants in widespread nonexudative atopic eczema’. B J Dermatol 1992; 126: 179-84. [A] Sheehan MP, Atherton DJ. ‘One-year follow up of children treated with Chinese medicinal herbs for atopic eczema’. Br J Dermatol. 1994; 130:488–493 Sheehan MP, Rustin MH, Atherton DJ, Buckley C, Harris DW, Brostoff J, Ostlere L, Dawson A. ‘Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis’. Lancet. 1992; 340:13–17. [B] Sheehan MP, Stevens H, Ostlere LS, Atherton DJ, Brostoff J, Rustin MH. ‘Follow-up of adult patients with atopic eczema treated with Chinese herbal therapy for 1 year.’ Clin Exp Dermatol. 1995; 20:136–140 Shi D, Ma A, Zheng H, Huo G, Yan H, Fu H, Qiu Y, Liu W. ‘Paeoniflorin inhibits the maturation and immunostimulatory function of allergen-induced murine dendritic cells’. Int Immunopharmacol. 2014 Apr; 19(2):221-32 52 Shi L, Fan PS, Fang JX, Han ZX. ‘Inhibitory effects of paeonol on experimental atherosclerosis and platelet aggregation of rabbit’. Chung Kuo Yao Li Hsueh Pao. 1988 Nov; 9(6):555-8 Shibata T, Morimoto T, Suzuki A, Saito H, Yanaihara T. ‘The effect of Shakuyakukanzo-to on prostaglandin production in human uterine myometrium’. Nihon Sanka Fujinka Gakkai Zasshi. 1996 May; 48(5):321-7 Shu X, Duan W, Liu F, Shi X, Geng Y, Wang X, Yang B. ‘Preparative separation of polyphenols from the flowers of Paeonia lactiflora Pall. by high-speed countercurrent chromatography’. Chromatogr B Analyt Technol Biomed Life Sci. 2014 Feb 1; 947-948:627. [B]

58

PEONY – A Reference for Patients and Professionals

Shu XK, Duan WJ, Liu W, Geng YL, Wang X, Yang BT, Yang P. ‘Chemical constituents from flowers of Paeonia lactiflora’. Zhong Yao Cai. 2014 Jan; 37(1):66-9. [A] Shu YZ, Hattori M, Akao T, Kobashi K, Kagei K, Fukuyama K, Tsukihara T, Namba T. ‘Metabolism of paeoniflorin and related compounds by human intestinal bacteria. II. Structures of 7S- and 7Rpaeonimetabolines I and II formed by Bacteroides fragilis and Lactobacillus brevis’. Chem Pharm Bull (Tokyo). 1987 Sep; 35(9):3726-33 Sugaya A, Suzuki T, Sugaya E, Yuyama N, Yasuda K, Tsuda T. ‘Inhibitory effect of peony root extract onpentylenetetrazol-induced EEG power spectrum changes and extracellular calcium concentration changesin rat cerebral cortex’. J Ethnopharmacol. 1991 May-Jun; 33(1-2):159-67 Sugaya E, Jin W, Sugaya A, Sunaga K, Tsuda T. ‘Inhibitory effects of peony root extract on the largeconductance calcium-activated potassium current essential in production of bursting activity’. J HerbPharmacother. 2006; 6(2):65-77 Sun WY, Wei W, Wu L, Gui SY, Wang H. ‘Effects and mechanisms of extract from Paeonia lactiflora andAstragalus membranaceus on liver fibrosis induced by carbon tetrachloride in rats’. J Ethnopharmacol. 2007 Jul 25; 112(3):514-23 Sun XM, Zhang ZW, Zheng Y. ‘Processing of medicinal peony’. Chung Kuo Chung Yao Tsa Chih. 1993 Jul; 18(7):411-3, 447 Sun XM, Zhang ZW, Zheng Y. ‘Processing of medicinal peony’. Chung Kuo Chung Yao Tsa Chih. 1993 Jul; 18(7):411-3, 447 Sunaga K, Sugaya E, Kajiwara K, Tsuda T, Sugaya A, Kimura M. ‘Molecular mechanism of preventive effect of peony root extract on neuron damage.’

J Herb Pharmacother. 2004; 4(1):9-20 53 Tabata K, Matsumoto K, Murakami Y, Watanabe H. ‘Ameliorative effects of paeoniflorin, a major constituent of peony root, on adenosine A1 receptormediated impairment of passive avoidance performance and long-term potentiation in the hippocampus’. Biol Pharm Bull. 2001 May; 24(5):496-500 Takahashi K, Yoshino K, Shirai T, Nishigaki A, Araki Y, Kitao M. ‘Effect of a traditional herbal medicine (shakuyaku-kanzo-to) on testosterone secretion in patients with polycystic ovary syndrome detected by ultrasound’. Nihon Sanka Fujinka Gakkai Zasshi. 1988 Jun; 40(6):789-92 Takahashi K, Kitao M. ‘Effect of TJ-68 (shakuyaku-kanzo-to) on polycystic ovarian disease’. Int J Fertil Menopausal Stud. 1994 Mar-Apr; 39(2):69-76.

Takeda S, Ishthara K, Wakui Y, Amagaya S, Maruno M, Akao T, Kobashi K. ‘Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis’. J Pharm Pharmacol. 1996 Sep; 48(9):902-5 Takeuchi T, Nishii O, Okamura T, Yaginuma T. ‘Effect of paeoniflorin, glycyrrhizin and glycyrrhetic acid on ovarian androgen production’. Am J Chin Med. 1991; 19(1):73-8

59

PEONY – A Reference for Patients and Professionals

Takeuchi T, Nishii O, Okamura T, Yaginuma T. ‘Effect of traditional herbal medicine, shakuyaku-kanzo-to on total and free serum testosterone levels’.

Am J Chin Med. 1989; 17(1-2):35-44 Takeuchi T. ‘Effect of shakuyaku-kanzo-to, shakuyaku, kanzo, paeoniflorin, glycyrrhetinic acid and glycyrrhizin on ovarian function in rats’. Nihon Naibunpi Gakkai Zasshi. 1988 Nov 20; 64(11):1124-39 Tamaya T, Sato S, Okada H. ‘Inhibition by plant herb extracts of steroid bindings in uterus, liver and serum of the rabbit.’ Acta Obstet Gynecol Scand. 1986; 65(8):839-42 Tanaka S, Takahashi A, Onoda K, Kawashima K, Nakaura S, Nagao S, Endo T, Ohno Y, Kawanishi T, Takanaka A, et al. ‘Toxicological studies on biological effect of herbal drug extracts on rats and mice–peony root, peach kernel, Japanese angelica root and Cnidium rhizom’. Yakugaku Zasshi. 1983 Sep; 103(9):937-55 Tanaka T. ‘Effects of herbal medicines on menopausal symptoms induced by gonadotropin-releasing hormone agonist therapy’. Exp Obstet Gynecol. 2001; 28(1):20-3 Tang J, Shi L. ‘The protective effects of paeonol on cultured neonatal rat heart cells during calcium paradox’. Chung Kuo Chung Yao Tsa Chih. 1991 Sep; 16(9):55760, 576 54 Tang JR, Shi L. ‘The inhibitory effects of sodium paeonol sulfate on calcium influx in the cultured neonatal rat heart cells during calcium paradox’.

Yao Hsueh Hsueh Pao. 1991; 26(3):161-5 Tani T, Inoue K, Arichi S, Ohno T. ‘Biopharmaceutical studies on crude drug preparations. I: Permeation of paeonol in a decoction and dry extract of Paeonia suffruticosa root cortex using an absorption simulator’.

J Ethnopharmacol. 1987 Sep-Oct; 21(1):37-44 Tomoda M, Matsumoto K, Shimizu N, Gonda R, Ohara N. ‘Characterization of a neutral and an acidic polysaccharide having immunological activities from the root of Paeonia lactiflora’. Biol Pharm Bull. 1993 Dec; 16(12):1207-10 Tsai HY, Lin HY, Fong YC, Wu JB, Chen YF, Tsuzuki M, Tang CH. ‘Paeonol inhibits RANKL-induced osteoclastogenesis by inhibiting ERK, p38 and NF-kappaB pathway’. Eur J Pharmacol. 2008 Jun 24; 588(1):124-33 Tsai TH, Chou CJ, Chen CF. ‘Pharmacokinetics of paeonol after intravenous administration in rats’. J Pharm Sci. 1994 Sep; 83(9):1307-9 Tsuda T, Sugaya A, Ohguchi H, Kishida N, Sugaya E. ‘Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by the cobalt focus epilepsy model’. Exp Neurol. 1997 Aug; 146(2):518-25 Tsuda T, Sugaya A, Ohguchi H, Kishida N, Sugaya E. ‘Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by the cobalt focus epilepsy model’. Exp Neurol. 1997 Aug; 146(2):518-25 Ul’ianov AM, Tarasov IuA, Liapina LA, Pastorova VE, Uspenskaia MS. ‘Effect of a peony root preparation on the status of the insulin and hemostatic system in

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animals during development of alloxan diabetes’. Vopr Med Khim. 1998 MayJun; 44(3):256-61 Wang C, Yuan J, Wu HX, Chang Y, Wang QT, Wu YJ, Liu LH, Wei W. ‘Paeoniflorin inhibits inflammatory responses in mice with allergic contact dermatitis by regulating the balance between inflammatory and anti-inflammatory cytokines’.

Inflamm Res. 2013 Dec; 62(12):1035-44 Wang CH, Wang R, Cheng XM, He YQ, Wang ZT, Wu C, Cao J. ‘Comparative pharmacokinetic study of paeoniflorin after oral administration of decoction of Radix Paeoniae Rubra and Radix Paeoniae Alba in rats’. J Ethnopharmacol. 2008 May 22; 117(3):467-72 55 Wang D, Tan QR, Zhang ZJ. ‘Neuroprotective effects of paeoniflorin, but not the isomer albiflorin, are associated with the suppression of intracellular calcium and calcium/calmodulin protein kinase II in PC12 cells’. J Mol Neurosci. 2013 Oct; 51(2):581-90.[B] Wang D, Wong HK, Feng YB, Zhang ZJ. ‘Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells’. Cell Mol Neurobiol. 2013 May; 33(4):521-9. [A] Wang QS, Gao T, Cui YL, Gao LN, Jiang HL. ‘Comparative studies of paeoniflorin and albiflorin from Paeonia lactiflora on anti-inflammatory activities’. Pharm Biol. 2014 Mar 19 (not published at time of filing) Wang S, Wang J, Bian H, Wang H, and Li P. ‘Clinical observation on total glucosides of paeony combined with sulfasalazine in treatment of anky-losing spondylitis’.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007, 27, 217–219 Wang XW, Chen MZ, and Xu SY. ‘The effects of total glucosides of peony (TGP) on T lymphocyte subsets’. Zhongguo Yao Li Xue Tong Bao. 1992, 8, 340–343, 314 Wang XW, Cheng MZ, and Xu SY. ‘Effects of total glucosides of peony on immune system’. Zhongguo Bing Li Sheng Li Za Zhi 7. 1991, 609–611 Wang XW, Wei W, Chen MZ, and Xu SY. ‘Mechanisms of immu-nomodulatory actions of total gluco-sides of peony in mice’. Zhongguo Yao Li Xue Tong Bao. 1990, 6, 363–366 Wang Y, Chen M, and Xu S. ‘Analgesic effect of total glucosides of Paeonia lactiflora’.

Zhongguo Yao Li Xue Yu Du Li Xue Za Zhi, 1988, 2, 6–10 Wang Y, Xing HY. ‘Clinical observation on effect of total glucosides of peony combined with methotrexate on rheumatoid arthritis’. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007 Sep 27(9):839-40 Wang YN, Zhang Y, Wang Y, Zhu DX, Xu LQ, Fang H, Wu W. ‘The beneficial effect of total glucosides of paeony on psoriatic arthritis links to circulating Tregs and Th1 cell function.’ Phytother Res. 2014 Mar; 28(3):372-81 Washida K, Itoh Y, Iwashita T, Nomoto K. ‘Androgen modulators from the roots of Paeonia lactiflora (paeoniae radix) grown and processed in nara prefecture, Japan’. Chem Pharm Bull (Tokyo). 2009 Sep; 57(9):971-4 56

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Watanabe H. ‘Candidates for cognitive enhancer extracted from medicinal plants: paeoniflorin and tetramethylpyrazine’. Behav Brain Res. 1997 Feb; 83(1-2):135-41 Wu B. ‘Studies on the Chinese drug cortex moutan radicis. Assay of paeonol in cortex moutan radicis’. Yao Hsueh Hsueh Pao. 1966 Feb; 13(2):145-8 Wu CF. ‘A review on the pharmacology of Paeonia lactiflora and its chemical components’. Chung Yao Tung Pao. 1985 Jun; 10(6):43-5. Review Wu HK, Sheu SJ. ‘Capillary electrophoretic determination of the constituents of paeoniae radix’. J Chromatogr A. 1996 Nov 8; 753(1):139-46 Wu HK, Sheu SJ. ‘Capillary electrophoretic determination of the constituents of paeoniae radix’. J Chromatogr A. 1996 Nov 8; 753(1):139-46 Yaginuma T, Izumi R, Yasui H, Arai T, Kawabata M. ‘Effect of traditional herbal medicine on serum testosterone levels and its induction of regular ovulation in hyperandrogenic and oligomenorrheic women’. Nihon Sanka Fujinka Gakkai Zasshi. 1982 Jul; 34(7):939-44.

Yamada K, Kanba S, Yagi G, Asai M. ‘Effectiveness of herbal medicine (shakuyakukanzo-to) for neurolepticinduced hyperprolactinemia.’ J Clin Psychopharmacol.

1997 Jun; 17(3):234-5 Yamahara J, Yamada T, Kimura H, Sawada T, Fujimura H. ‘Biologically active principles of crude drugs. II. Anti-allergic principles in “Shoseiryu-To” antiinflammatory properties of paeoniflorin and its derivatives’.

J Pharmacobiodyn. 1982 Nov; 5(11):921-9 Yamamoto K, Hoshiai H, Noda K. ‘Effects of shakuyaku-kanzo-to on muscle pain from combination chemotherapy with paclitaxel and carboplatin’. Gynecol Oncol. 2001 May; 81(2):333-4 Yamasaki K, Tamaki T, Sankawa U, Shibata S. ‘Biosynthesis of paeonol’. Yakugaku Zasshi. 1976 Sep; 96(9):1103-6 Yang XG, Peng B, Zhang GH, Wei LL, Nie SF, Pan WS. ‘Studies of the pharmacokinetics of paeoniflorin in two Jing-Zhi-Guan-Xin formulations after oral administration to beagle dogs’. J Pharm Biomed Anal. 2006 Apr 11; 41(1):320-4.

Yasuda T, Kon R, Nakazawa T, Ohsawa K. ‘Metabolism of paeonol in rats’.

J Nat Prod. 1999 Aug; 62(8):1142-4 57 Yen PH, Kiem PV, Nhiem NX, Tung NH, Quang TH, Minh CV, Kim JW, Choi EM, Kim YH. ‘A new monoterpene glycoside from the roots of Paeonia lactiflora increases the differentiation of osteoblastic MC3T3-E1 cells’. Arch Pharm Res. 2007 Oct; 30(10):1179-85 Yoshida T, Sawa T, Ishiguro T, Horiba A, Minatoguchi S, Fujiwara H. ‘The efficacy of prophylactic Shakuyaku- Kanzo-to for myalgia and arthralgia following carboplatin and paclitaxel combination chemotherapy for non-small cell lung cancer’. Support Care Cancer. 2009 Mar; 17(3):315-20 Yoshihisa Y, Furuichi M, Ur Rehman M, Ueda C, Makino T, Shimizu T. ‘The traditional Japanese formula keishibukuryogan inhibits the production of

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inflammatory cytokines by dermal endothelial cells’. Mediators Inflamm. 2010; 2010:804298 Yoshikawa M, Uchida E, Kawaguchi A, Kitagawa I, Yamahara J. ‘Galloyloxypaeoniflorin, suffruticosides A, B, C, and D, five new antioxidative glycosides, and suffruticoside E, A paeonol glycoside, from Chinese moutan cortex’ Chem Pharm Bull (Tokyo). 1992 Aug; 40(8): 2248-50 Yu J, Lang HY, Xiao PG. ‘The occurrence of paeoniflorins and paeonols in Paeoniaceae’. Yao Hsueh Hsueh Pao. 1985 Mar; 20(3):229-34 Yu J, Xiao PG. ‘Ontogenetic chemical changes of the active constituents in mudan (Paeonia suffruticosa) and shaoyao (P. lactiflora)’. Yao Hsueh Hsueh Pao. 1985 Oct; 20(10):782-4 Zhang HF, Xiao WG, Hou P. ‘Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus’. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011 Apr; 31(4):476-9 Zhang HY, Ge N, Zhang ZY. ‘Theoretical elucidation of activity differences of five phenolic antioxidants’. Chung Kuo Yao Li Hsueh Pao. 1999 Apr; 20(4):363-6 Zhang J, Dou W, Zhang E, Sun A, Ding L, Wei X, Chou G, Mani S, Wang Z. ‘Paeoniflorin abrogates DSSinduced colitis via a TLR4-dependent pathway.’

Am J Physiol Gastrointest Liver Physiol. 2014 Jan 1; 306(1):G27-36 Zhang LH, Xiao PG, Huang Y. ‘Recent progresses in pharmacological and clinical studies of paeonol’. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 1996 Mar;16(3): 187-90. Review 58 Zhang LL, Wei W, Wang NP, Wang QT, Chen JY, Chen Y, Wu H, Hu XY. ‘Paeoniflorin suppresses inflammatory mediator production and regulates G protein-coupled signaling in fibroblast-like synoviocytes of collagen induced arthritic rats’. Inflamm Res. 2008 Aug; 57(8):388-95 Zhang Q, Wang B. ‘Determination of paeoniflorin in white peony root and fufang baishao tablets’. Chung Kuo Chung Yao Tsa Chih. 1991 Sep; 16(9):542-3, 575 Zhang W, Dai SM. ‘Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas in rheumatoid arthritis’. Int Immunopharmacol. 2012 Sep; 14(1):27-31 Zhang WG, Zhang ZS. ‘Anti-ischemia reperfusion damage and anti-lipid peroxidation effects of paeonol in rat heart’. Yao Hsueh Hsueh Pao. 1994; 29(2):145-8 Zhang X J, Chen H L, Li Z, Zhang H, Xu H X, Sung J, and Bian Z X. ‘Analgesic effect of paeoni-florin in rats with neonatal maternal separation-induced visceral hyperal-gesia is mediated through adenosine A1 receptor by inhibiting the extracel-lular signal-regulated protein kinase (ERK) pathway’. Pharmacol.

Biochem. Behav. 2009. 94, 88–97

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Zhao M, Liang GP, Tang MN, Luo SY, Zhang J, Cheng WJ, Chan TM, Lu QJ. ‘Total glucosides of peony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells’. Clin Immunol. 2012 May; 143(2):180-7. [A] Zhao M, Liang G, Luo S, Lu Q. ‘Effect of total glucosides of peony on expression and DNA methylation status of ITGAL gene in CD4(+) T cells of systemic lupus erythematosus’. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2012 May; 37(5):463-8. [B] Zheng YQ, Wei W, Zhu L, Liu JX. ‘Effects and mechanisms of Paeoniflorin, a bioactive glycoside from peony root, on adjuvant arthritis in rats’. Inflamm Res. 2007 May; 56(5):182-8 Zhou H, Bian D, Jiao X, Wei Z, Zhang H, Xia Y, He Y, Dai Y. ‘Paeoniflorin protects against lipopolysaccharide induced acute lung injury in mice by alleviating inflammatory cell infiltration and microvascular permeability’. Inflamm Res. 2011 Oct; 60(10):981-90 Zhou Q, and Li ZG. ‘Pharmacology and therapeutic usages of total glucosides of peony in autoimmune diseases’. Zhongguo Xin Yao Yu Lin Chuang Za Zhi. 2003, 22, 687–691 59 Zhou Y, Wang H, Li YS, Tao YW, Zhang JY, Zhang ZQ. ‘Paeoniflorin increases betadefensin expression and attenuates lesion in the colonic mucosa from mice with oxazolone-induced colitis’. Yao Xue Xue Bao. 2010 Jan; 45(1):37-42 Zhou Z, Lin J, Huo R, Huang W, Zhang J, Wang L, Sun Y, Shen B, Li N. ‘Total glycosides of peony attenuated functional maturation of dendritic cells via blocking TLR4/5 signalling in vivo’. Int Immunopharmacol. 2012 Nov; 14(3):275-82 60

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Index

A Abdominal masses 14, 15, 16 pain 14, 15, 27 Abscesses 15 Acetone extract 32 Acetylcholine 28, 35 Adenosine receptor 35 Adhesions (gynaecological) 27 Albiflorin 17, 22, 26, 32, 35, 39 Alcohol extracts 25 Alisma root 45 Allergic reactions 41 Allergy 38, 44 Alopecia 39 Alpha-1&2- adrenergic 34 Alzheimer’s disease 34 Amenorrhoea (absent periods) 15 Amoxicillin 21 Androgen 19, 29, 30, 31 Angelica sinensis 26, 34, 45 Anti-allergy 17 Anti-androgenic 29 Anti-arthritic 19 Antibiotic 21 Anti-coagulant 19 Anti-convulsant 19, 32 Anti-cramp 28 Anti-depressant 19, 25 Anti-epileptic 32, 49 Anti-hyperglycaemic 19 Anti-inflammatory 17, 19, 27, 36–42, 44 Antioxidant 40

Anti-psychotics 31 Anti-spasmodic 12, 28 Anti-viral 44 Arachidonic acid 27, 28 Aromatase 30 Arthralgia 40 Arthritis 37, 38, 39, 47 Asclepius 5 Astragalus membranaceus 40, 45 Atherton, Dr. David 42 Atractylodes Iancea 45 Atropine 28 Ayurvedic 10, 11

B Bacteria 19, 21, 30, 42 Bacteroides fragilis 20 Bai shao yao. See Peony, White Banks, Sir Joseph 9 Bao mai 14 Benzoylpaeoniflorin 22, 29, 36 Black cohosh 12 Bladder 10, 12 Blood, cells, white 27, 36, 38, 41, 44 clotting 44 ‘cooling’ 11, 13, 16 ‘deficiency’ 15 in Chinese Medicine 13 ‘invigorating’ 13, 16 ‘tonifying’ 14 Boils 15 Brain 31, 32–35, 36 British Pharmacopoeia 8 65

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C Calcium 6, 22, 32, 34, 36 Cancer 29, 38, 40, 41 Carboplatin 40 Cerebral cortex 32, 35 Chemokines 36, 37, 38, 44 Chemotherapy 40 China 6, 9, 20 Chinese Pharmacopoeia 18, 39 Chi shao yao. See Peony, Red Chlorpromazine 31 Chorea 12 Chujo-to (Kampo formula) 26 Chumash Indians 27 Cinnamon 28, 34 Colic 11, 27 Colitis 40 Convulsions 11, 12 febrile 34 Cramp 28 Cyclo-oxygenase (COX) 36 Cyclophosphamide 39 Cysts 14 Cytokines 36, 37, 38, 41, 43

D Dangguishaoyao- san 45 Delta-4 androstenedione 30 De Materia Medica 10 Dementia 34 Dendritic cells 37, 44 Depression 32 Dermatitis 17, 43, 47 Desbenzoylpaeoniflorin 43 DHEA 26 Dialysis 28 Dioscorides 10 Dizziness 14, 25 Dong quai. See Angelica sinesis DOPAC 31 Dopamine 31 66

DOPEG 31 Dosage 28, 39, 49 Duodenal spasm 28 Dysmenorrhoea (period pains) 15, 27, 47

E Eclectic physicians 12 Eczema 16, 25, 42, 44, 47 EEG 32 Ellingwood, Dr. Finley 12 Endometriosis 26, 27, 29, 47, 49 Epilepsy 11, 12, 25, 32–36, 47 Essence (strength) 14 Europe 9, 45

F Falling sickness. See Epilepsy Felter & Lloyd, Drs. 12 Fever 10, 16, 19, 39, 44 Fibroids 14, 26, 27, 29, 47, 49 Flushes 16, 25, 26 Forsythia 36, 45 Free fatty acids 42 Furor uterinus (agitation of the womb) 11

G Galen 10 Gallic acid 23, 37 Gallotannin 22, 34 Gerard, John 10 Ginger 34 Ginsenoside 43 Glutamate 34, 35 Glycyrrhetinic acid 28, 30 Glycyrrhiza glabra 20 Glycyrrhiza uralensis 20 Glycyrrhizin 30 Golden Seal 41 G-protein 37

PEONY – A Reference for Patients and Professionals

Great Ormond St Hospital 17, 42 Gynaecological uses 10, 12, 15, 16, 25, 26, 45

H Hall, John 32 Han Dynasty 8, 19 Headache 25 Heavenly water 14 Helicobacter pylori 21 Herbalists 1, 10, 20, 39, 45 Himalayan Peony 11 Hippocampus 35 Hirsutism 29 HRT 49 Hydrastis canadensis 41 Hydrogen peroxide 36 Hysteria 11–12 Hystos 11

I Immune cells 27, 36, 38, 41, 42, 44 India 6 Inflammation 36, 36–42, 44 influenza 41 insulin resistance 41 Interleukin (IL) 37, 39, 41, 44 ‘Invigorating’ effect 13, 15 Ischaemia 35 Itching 43

J Japan 6, 20, 26, 29, 30, 34 jaundice 10

K Kew Gardens 9 Kundapuspa 14

L Lactobacillus brevis 20 Learning 19, 34, 35 Leflunomide 38 Leonurus heterophyllus 45 Lethargy 14 LH 31 Ligusticum 45 Liquorice 19, 20, 27, 29–30, 34, 39, 40 Liver 16, 19, 20, 38, 40, 45 Lymphocytes 38

M Macrophages 27, 42 Materia Medica 11, 14 Memory 19, 34 Menopause 14, 25–27, 42 Menorrhagia (heavy periods) 29 Menstruation 10, 12, 14, 16, 19, 25, 27, 29, 45 Metabolic syndrome 41 Methanol extract 32 Methotrexate 38 Metronidazole 21 Microglial cells 36 Mitochondria 35 Mono-amine-oxidase 26 Monocyte chemoattractant proteins (MCP) 41 Monoterpene 6, 18, 22 Moutan (P. suffruticosa).

See Peony, Moutan Mu dan pi See Peony, Moutan Myalgia 40

N Nervous system 12, 25, 35, 36 Neurodegenerative disorders 35 Neuroleptics 31 Neuro-protection 26 67

PEONY – A Reference for Patients and Professionals

Neurotransmitters 31 Nucleus basalis magnocellularis 35

O Obesity 41 Oestradiol 30 Oestrogen 26, 30, 31, 49 Osteoblasts 27 Osteoclasts 27 Osteoporosis 26 Ovaries 19, 26, 27, 29, 30, 31

P Paclitaxel 40 Paeon 5 Paeonia albiflora 9 Paeonia californica 27 Paeonia edulis 9 Paeonia emodi 11 Paeonia lactiflora 5, 7, 8, 9, 17, 22–23, 23, 25, 30, 43 Paeonia mascula 10 Paeonia officinalis 9, 12 Paeonia suffruticosa 7, 17, 26, 28, 43. See also Peony, Moutan Paeonia veitchii 7 Paeoniflorin 18–19, 25, 29, 30, 32, 34, 35, 37, 39, 40, 43, 45 Paeonilactone 23, 36 Paeonimetabolins 20, 32 Paeonol 17–18, 27, 43 Pallas, Peter 9 Palpitations 14 Parkinson’s disease 35 PCOS. See Polycystic ovarian disease Pentagalloylglucose 17, 29, 32 Peony Moutan 7, 13, 16 Red 7, 13, 15 tincture 49 68

tree. See Peony, Moutan White 7, 8, 13, 15 Peony/liquorice combination 19, 20, 21, 26, 27, 28, 30–31, 40, 45 Peppermint oil 28 Periods heavy/painful. See Dysmenorrhoea none. See Amenorrhoea Peripheral neuropathy 40 Pertussis (whooping cough) 12 Phytooestrogenic herbs 49 PMS (pre menstrual syndrome) 28 Polycystic ovarian disease (PCOS) 29–30, 47, 49 Poria 28, 45 Portals of entry 41 Post natal problems 32 Potassium 32 Prazosin 34 Prostaglandins 27, 37 Prunus persica 28 Psoriasis 47 Psoriatic arthritis 39 Psoriatic arthropathy 47

R Ranunculaceae 5 Red clover 49 Red peony 7. See Peony, Red Rehmannia glutinosa 45 Respiratory infections 41 Rheumatoid arthritis 37, 38, 47 Risperidone 31 Robinson, Dr. M 11 Rosa chinensis 45

S Sanskrit 14 Schizophrenia 31 Scopolamine 34 Seizures 11, 16, 32

PEONY – A Reference for Patients and Professionals

Sepsis 42 Sertindole 31 Sex-drive 31 Shakuyaku kanzoto 19.

See also Peony/liquorice combination Shao Yao 8 Shaoyao gancao tang 19.

See also Peony/liquorice combination Shen Nong Ben Cao Jing 8 Shen (spirit) 14 Side-effects 31, 38 of peony 49 Sjogren’s Syndrome 39, 47 Skin disorders/diseases 16, 25, 37, 42–44, 45, 47 dry 14 inflammation 25, 37, 43, 47 SLE. See Systemic lupus erythematosus Spasms 12, 15 Spirit. See Shen Steep Holme 10 Stomach ulcers. See ulcers Stroke. See Ischaemia Sugar 42 Surfactant effect of liquorice 22 Sweating 15 Synovium 37, 38 Systemic lupus erythematosus (SLE) 37, 38, 39, 47

T

Testosterone 19, 30–32 Tonic 25 Traditional Chinese medicine (TCM), peony in 13–14 Traditional Herbal Registration Number 49 Treg cells 39 Tumour necrosis factor (TNF) 37, 39, 40, 42, 43 Tumours 14 Turner, William 10

U Ulcers 38 stomach 21, 40 Uterine disorders 11, 15

V Vaginal discharge 15

W Warfarin 49 Weight gain 29 White blood cells 27, 41 White peony. See Peony, White

Y Yohimbine 34

Z Zemaphyte 43 Zeus 5 Zhang Zhongjing 19 Zizyphus 34

Tamoxifen 49 T-cells 38, 44

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Stuart FitzSimons

(MNIMH Dip. Phyt; Medical Herbalist)

Stuart FitzSimons MNIMH has been a medical herbalist for nearly 30 years, and unusually, during that time his work has engaged him in all aspects of herbal medicine.

Apart from setting up and running clinics in different towns in the UK he lectured for nearly 10 years, on a part-time basis, for the School of Herbal Medicine (Sussex), taught at training clinics and acted as an examiner for the School and the National Institute of Medical Herbalists.

Stuart has also formulated products and advised companies in the herbal industry on product placement and promotion. He has worked closely with new European legislation concerning herbal products and has written extensively for newspapers and magazines.

Stuart has recently returned to his native south Wales and has set up a clinic in Carmarthen. He has a special interest in the treatment of eczema and the menopause and has a long-term interest in the use of the medicinal mushrooms and their components in the treatment of cancers and immune disorders.

Feel free to get in touch through www.plantasmagorical.com.

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PEONY One of the best kept secrets of the herbalist’s dispensary.

A herb for women.

One of the safest herbs available.

A herb with centuries of continuous use.

Every now and again, a herb will emerge from the world of the herbal clinic and find its way to public attention. Just such a herb is peony, truly one of the best kept secrets in the herbal world.

This is a herb with centuries of continuous use and a record of success and safety that beggars belief. It is used particularly in the treatment of gynaecological and menopausal problems and is perfectly safe in combination with the major drugs used in those areas of medicine.

ISBN 978-0-9574238-2-4