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TREATMENT OF ITP WITH CHINESE MEDICINE (2/2)


  • BLOOD STASIS HYPOTHESIS FOR CHRONIC AUTOIMMUNE THROMBOCYTOPENIA

  • It has been proposed by some authors that the symptomatic manifestation of purpura signifies a blood stasis syndrome and that the chronic disease, in particular, should be treated mainly by vitalizing blood circulation.  One of the first descriptions of this approach was from the Heilongjiang College of Traditional Chinese Medicine, published in 1981 and then republished in English in 1983 (15).  The authors reported that in a group of 200 ITP patients, there were 46 who had chronic cases and, of these, 30 had “varying degrees of blood stasis.”  The remaining 16 chronic cases had varying degrees of spleen qi deficiency with inability to restrain the blood and yin deficiency with glowing fire.

  • The symptoms of blood stasis were: bruising and petechia; dry, lusterless hair; dark facial color; purplish congestion in the eye vessels; lower eyelid shows purplish dark case; pulse was thready and/or astringent.  Two or more of these signs were needed to place an ITP patient in the diagnostic category of blood stasis.  Since the purpura signs are to be expected in chronic cases of ITP in those seeking treatment, only one other sign would be necessary to yield the diagnosis.  The proposed formula was: millettia, red peony, san-chi flowers, rubia, tang-kuei, salvia, codonopsis, jujube, eclipta, rehmannia.  If there was a high level of bleeding, the formula could be modified by temporarily removing red peony and salvia and adding agrimony, lotus node, charred hair, and trachycarpus.  Additional anti-hemorrhage herbs might be added according to their reputation for treating a specific site of bleeding.  The authors claimed that improvements occurred in all but 3 of the 30 cases of blood stasis that were so treated.  The average duration of therapy was 85 days (about three months) and the platelet levels increased from 41 before treatment to 85 after treatment. 

  • The authors of this report quoted earlier physicians as stating that one should not just attempt to stop bleeding, but should move or circulate the blood.  This should be done whether the blood is fresh or black, and whether the condition is associated with cold or heat.  The authors then relayed their own experience:

  • In the beginning stage [of treatment] if we use the principle of following the etiology (e.g., kidney yin deficiency with uprising and flaming of deficiency fire; spleen deficiency with loss of control and blood not returning to the vessels), we will have some patients respond poorly to this treatment.  These patients will present the signs of blood stasis....Chinese researchers using animal experiments found that the treament method of vitalizing blood and dissolving blood stasis inhibit the formation of IgG and regulates the T-cell balance....The treatment of vitalizing blood and dissolving blood stasis lowers capillary fragility and decreases the permeability of vessels and, in this way, resistance to bleeding is increased.

  • In two of the studies cited in Table 4, the base formula that is applied is: cnidium, salvia, tang-kuei, carthamus, millettia, red peony, leonurus.  The ingredients in common here are salvia, red peony, millettia, and tang-kuei.

  • The principle of using a blood-vitalizing therapy for ITP, incorporating many of the same herbs, was mentioned recently in a reported clinical trial  16).  The herb therapy was comprised of astragalus, atractylodes, polygonatum, tang-kuei, millettia, red peony, moutan, carthamus. According to the authors, 2/3 of the patients showed improvements, and the average platelet count for the whole group increased from 34 to 57, while the IgG level decreased from 195 to 122.  In addition, the researchers measured hepatoglobin, a substance produced by the liver that is elevated in patients with ITP; this substance declined by 1/3 following the herb treatment.  The authors expressed the view that ITP had the characteristic of a dysfunctional immune system which could be corrected by tonifying the qi (with astragalus, polygonatum, and atractylodes; this method of therapy promotes the correct qi and reduces the pathological qi) and invigorating blood circulation (which inhibits autoimmune attacks).

  • A disorder similar in symptoms to primary ITP, idiopathic multifocal bleeding and platelet aggregation defect (IMBPAC), was addressed with a blood-vitalizing therapy by physicians working at the Tongji Medical University in Wuhan (17).  They used Xiaoyu Zhixue Pian (Reduce Stagnation, Regulate Blood Tablets) made with astragalus, codonopsis, licorice, peony, tang-kuei, and persica.  The herbal material, corresponding to 1.2 grams crude herb per tablet, was administered 5-8 tablets each time, 2-3 times daily.  They reported a hemostatic effect in most patients in 5-7 days (total treatment time was four months).  Instead of relying on hemostatic herbs, the formula boosts the qi and vitalizes blood circulation

  • NORMALIZING PLATELET FUNCTIONS

  • There is considerable concern raised in modern medical practice about altering platelet functions.  During the 20th century, the primary cause of premature death in the Western world was a blood clot that either caused a heart attack or stroke.  As a result, the stickiness of platelets, which contributes to forming the blood clot, has been deemed one of the most serious pathological problems.  Patients who experienced a non-fatal blood clot event would often be placed on life-long therapy to inhibit platelet sticking, so as to avoid a second event.

  • The ease with which a clot could form in the population (especially those past 45 years of age) appears to be due to several factors, including excess blood sugars and lipids, high oxidation status (lipid peroxidation products in the membranes), and the influence of smoking, excessive alcohol consumption, use of exogenous estrogens (menopause treatment), and the effects of sedentary lifestyle.  These factors help explain why there was such a dramatic increase in fatality due to blood clots during the 20th century compared to the 19th century, and also why there were declines in incidence of these problems in the latter part of the 20th century after recommendations were made for adjusting life style and using drugs to inhibit clotting.

  • However, one effect of the high incidence of clotting and the corresponding medical attention to the clotting problem is to generate an image of platelets as being inherently harmful and to view substances that alter bleeding and clotting to be something that must be strictly controlled medically.  In relation to herbal medicine, this has meant serious concerns about using herbs that influence clotting (many of them do if the dosage is high enough), and especially using these herbs along with medical therapies that influence clotting.

  • Chinese physicians have emphasized the use of blood-vitalizing herbs ever since Wang Qingren, in the first half of the 19th century, proposed that blood stasis was a major factor in several serious diseases.  His blood-vitalizing formulas had dramatic effects in many cases, and were widely adopted for use during the 20th century when the cardiovascular diseases became prominent.

  • One of the issues that was raised was whether or not blood-vitalizing herbs might worsen, or even induce, bleeding; the other was whether or not hemostatic herbs might worsen or induce undesired blood clotting.  A traditional theory, that some bleeding disorders are due to blood stasis, meant that Chinese doctors would sometimes treat bleeding with herbs that had a reputation for getting rid of clotted blood (e.g., bruising as occurs with injuries).  Those herbs were shown in some pharmacology experiments to reduce platelet aggregation, which, one would think, would worsen rather than aid bleeding.  An explanation for the apparent contradiction between clinical observations and the laboratory experiments is that at low dosage the herbs can regulate platelet function and stop bleeding when the function is deficient, while at very high doses (as used in laboratory experiments and some decoctions), the herbs specifically reduce platelet sticking.

  • One of the apparent paradoxes of modern Chinese herbal medicine is the use of san-chi (Panax notoginseng) to treat bleeding and also to help resolve blood clots and vitalize blood circulation.  Other herbs that might have this effect are agrimony, rubia, and leonurus.  While this diversity of actions may appear contradictory, it is not inherently so.  For example, if the dietary and other lifestyle factors yield platelets which function abnormally, then lifestyle changes and herbs that help normalize their functions can have several beneficial effects.  Normal-acting platelets will not be likely to spontaneously clot in the blood vessels, but they will clot promptly when there is a damaged vessel causing leakage of blood.  Herbs that regulate blood circulation might normalize platelet functions and, at the same time, influence blood vessel dilation, vessel wall integrity, and other factors.  The idea that the Chinese herbs will have a normalizing function, rather than causing an adverse effect, is one which is difficult to prove, leaving some question in the minds of concerned practitioners and patients.  Chinese physicians, for the most part, have adopted the view that the use of the herbs to regulate blood conditions is safe.

  • KEY HERBS FOR REGULATING BLOOD

  • Table 5 presents hemostatic herbs that are included in several of the formulas for treating ITP. There are a wide range of botanical sources represented here (each herb being from a different plant family) and wide range of active constituents that might ultimately contribute to hemostatic action, including essential oils, flavonoids, saponins, and alkaloids.  Other herbs that are used to treat bleeding, such as fried schizonepeta, typha, and the thistles (breea and cirsium), are not commonly used for ITP, suggesting that the physicians have focused on a small group of herbs that may be more suited to treating this particular disorder.

  • The possible mechanisms of action of the hemostatic herbs include:

  • ·       increasing the production of platelets

  • ·       promoting the ability of platelets to aggregate when there is blood leakage

  • ·       decreasing capillary permeability

  • ·       contracting peripheral blood vessels

  • ·       inhibiting autoimmune attack against platelets

  • These effects should be expected to be observed within a few days of administering the herbs.  In most of the Chinese medical reports, improvement in symptoms (such as spontaneous bleeding and petechia) were observed within about 10 days.  Changes in bone-marrow functions and autoimmune processes may require somewhat longer therapy, at least several weeks (typically one to three months treatment time), with increasing effect in responsive patients.  The reported changes include higher platelet counts and lower IgG levels.   Three groups of active constituents are known to have some hemostatic effects and may influence autoimmune processes:

  • ·       anthraquinones, found in rubia and rumex and also an ingredient of rhubarb root (which has hemostatic effects, but is not included in the ITP formulas)

  • ·       flavonoids, found in eclipta and agrimony, and also in scute (used to inhibit bleeding but rarely in the ITP formulas)

  • ·       alkaloids, found in lotus (all plant parts), eclipta, and san-chi


The role of essential oils (which usually dilate vessels; some might increase bleeding), triterpenes, and saponins found in several of the herbs remains unknown.  One of the most frequently-used herbs in the formulas, raw rehmannia, contains iridoid glycosides that have hemostatic effects (see: Rehmannia).  The same active constituents are found in gardenia, which is mentioned in a few of the ITP treatments, as well as in scrophularia and cornus (only rarely mentioned in the ITP formulas).


Table 5: Hemostatic Herbs Used for ITP.


All of the herbs listed here are reported to shorten bleeding time in laboratory testing. 

























































Common Name

Pinyin

Botanical Name

Active Constituents

Comments

Agrimony xianhecao

Agrimonia pilosa;


agrimonin (essential oil); agriminolide (flavonoid)

Agrimonin has been developed into a hemostatic drug in China, but pharmacology studies give conflicting results.  The clinical effectiveness is not confirmed.

Biota tops

ceboye

Biota orientalis


essential oils: juniperic acid, thujone

Biota leaves are frequently used (applied topically and taken internally) to treat alopecia, which is thought to involve an autoimmune disorder.

Eclipta hanliancao

Eclipta prostrata


(ecliptine, wedelolactone)

Though classified as a yin tonic, it is often used to control bleeding.  The flavonoids may reduce capillary permeability.

Imperata

maogen

Imperata cylindrica


triterpenes: simiarenol, fernenol

The triterpenes reduce inflammation; there may be flavonoids in the flower that reduce capillary permeability.

Lotus node

oujie

Nelumbo nucifera


alkaloids: nuciferine, liriodenine

The alkaloids shorten bleeding time.

Rubia

qiancaogen

Rubia cordifolia


alizarin, purpurin


anthraquinones

The herb extract dilates vessels and shortens bleeding time.

Rumex

(yangdi; suanmo)

Rumex spp.


anthraquinones: emodin

Although not frequently mentioned in the Chinese literature, the rumex plants are recommended for bleeding in association with blood stasis.

San-chi

sanqi

Panax notoginseng


dencichine

This is the key ingredient in the popular hemostatic remedy Yunnan Baiyao.

Sanguisorba

diyu

Sanguisorba officinalis


saponins: sanguisorbin

Sanguisorba is especially used in cases of rectal bleeding.


In development of herbal formulas for ITP, there may be some influence of what has been called the “doctrine of signatures” in selecting some of the herbs.  The hallmark of the disease, as seen from the traditional viewpoint without laboratory tests, is the petechia with a red to purple color.  Several of the herbs recommended for the treatments also have a red to purple color.  Examples are the purple-colored (zi) lithospermum (zicao) and perilla stem (zisugeng), the cinnabar-colored (dan) salvia (danshen) and moutan (mudanpi), and the red-colored (chi or hong) herbs red peony (chishao) and carthamus (honghua).  The herb jujube used in the treatments may have been the red one (hongzao), rather than the more common black one (dazao), though the variety was not clearly specified in the literature.  Similarly, there is the blood-colored millettia (jixueteng; xue = blood), and the reddish herbs which are noted for their color in their botanical names (Sanguisorba; sangui = blood; Rubia; rubi = red).  Isatis leaf, used in some formulas, is the source of the purple dye indigo. The yin-tonic lycium fruit, which is used in some formulas, is a bright-red colored fruit, while the astringent cornus fruit has a purplish color.  It is not clear to what extent the red to purple color of the herbs has influenced their selection for treatment of ITP by modern practitioners, but the color of herbs is known to have been a factor in the early development of the Chinese herbal medical system.


DOSAGE


Information about herb dosage was not available for all the studies, but in many cases doses of herbs used in decoction were given.  The description for most of the treatments is use of “heavy dosage” of the individual herbs, with amounts of 9-15 grams per day of each ingredient, sometimes more.  Typically, the herbal formulas (or at least, the portion described) would contain 8-10 ingredients, with possible additions (for particular symptoms or disease manifestation) of 1-3 other ingredients.  As a result, the decoctions would be made from a minimum of about 100 grams to a maximum of about 150 grams, with 125 grams being typical.  In the West, it is common to use dried extracts in place of decoctions; these dosages correspond to about 18-27 grams per day.  In most of the reports, the decoctions were divided into two doses per day.  It is understood that children receive lower doses, based on their age.  In the Pharmacopoeia of China, a dosage schedule relating children’s dosage to adult dosage is presented as follows:


































Age

Dosage Range

1-2 years

1/5-/14 of the dose for adult

2-4 years

1/4-1/3 of the dose for adult

4-6 years

1/3-2/5 of the dose for adult

6-9 years

2/5-1/2 of the dose for adult

9-14 years

1/2-2/3 of the dose for adult

14-18 years

2/3 to full dose for adult



A good example of dosing for adults and for children is offered by examining two studies published in 1991, one (7) aimed at treating adults (ages 18-53) and the other (8) aimed at treating children (ages 6 months to 13 years).  Both studies involved decoctions that had a basic formula which could be modified for the individual cases.  The adult formula was based on tonifying the spleen and kidney yang and was comprised of 12 grams each of psoralea, drynaria, cuscuta, atractylodes, and hoelen; 15 grams of tang-kuei; and 20 grams each of astragalus, codonopsis, and rehmannia.  The total dosage of the base formula was 135 grams.  Modifications to the formula involved adding from 10-30 grams of one or two herbs, such as agrimony or salvia.  For the children’s study, the formula was based on vitalizing blood circulation and the formula was: 15 grams of leonurus; 10 grams each of salvia, red peony, and millettia; and 5 grams of cnidium.  The base formula dosage was 50 grams.  Modifications involved adding from 1 to 6 herbs, with dosages of 5-15 grams each.  In this case, the dosage was about one-third the adult dosage, which corresponds to the Pharmacopoeia dosing for ages 2-6 years of age.  These two formulas also illustrate a difference in therapeutic approach; the young children generally suffer from the early stage of an acute ITP which is treated here by the principle of invigorating blood circulation while the older patients, many of whom suffered the disease chronically and therefore suffer the effects of the persistent disease and the medical treatments (including steroids used before) were treated with herbs that tonify the liver, kidney, and spleen. 


In one study (5) of acute ITP (treatment time 10 days), a very large dose of agrimony root (whole herb is more commonly used) is given.  The dosing of this ingredient in decoction form is described as follows: 100 grams for adults, 50 grams for 7-12 years, 30 grams for 5-6 years, 20 grams for 2-4 years, 10 grams for infants. 


In two of the ITP reports (and the one report on IMBPAD), pills and tablets were used rather than decoctions.  The pills for ITP were made from powdered herbs, consumed in the amount of 5 grams each time, twice daily; the tablets for ITP were poorly described; they contained 380 mg per tablet, with a dosage of 12-18 tablets per day, for a daily intake of about 5-7 grams per day.  It is common practice to use about 5-10 times as much herb to make a decoction as to make a pill when treating the same disorder, so these dosages fit the usual pattern.  For IMBPAD, the dosages reported for the tablets corresponded to 12-29 grams per day of crude herbs, but the processing to yield the tableted material was not specified.  The limited reporting of using non-decoction forms such as these makes it difficult to know if they are as effective as the high dosage decoctions.


REFERENCES



  • 1.     Huang Zhengqiao, et al., Study on the relationship between TCM differentiation of primary thrombocytopenic purpura and immunology, Journal of Traditional Chinese Medicine 1991; 32(10): 607-609.

  • 2.     Zhou Yongming, et al., Clinical observation on the principle of strengthening spleen, tonifying kidney, and purging fire for primary thrombocytopenic purpura, Shanghai Journal of Traditional Chinese Medicine 1991; (3): 1-3.

  • 3.     Huang Zhengziao, et al., Clinical study on initial thrombocytopenic purpura, China Journal of Traditional Chinese Medicine and Pharmacy, 1993; 8(2): 11-14.

  • 4.     Zeng Fanchang, et al., Clinical study of Zhinu-1 and Zhinu-2 in treating 61 patients with ITP, Chinese Journal of Integrated Chinese and Western Medicine 1996; 16(4): 207-209.

  • 5.     Fruehauf H, The Treatment of Difficult and Recalcitrant Diseases with Chinese Herbs, 1997 ITM, Portland, OR.

  • 6.     Han Weigang and Qi Rongfang, 27 cases of primary thrombocytopenic purpura treated by traditional Chinese medicine, Gansu Journal of Traditional Chinese Medicine 1995; 8(4): 11-12.

  • 7.     Gao Xiang, et al., Treatment of chronic primary thrombocytopenic purpura with Chinese herbs, Journal of Traditional Chinese Medicine 1991; 32(3): 24.

  • 8.     Cui Shuzhen, et al., Treatment of infant persistent thrombocytopenic purpura with Chinese herbs, Jilin Journal of Traditional Chinese Medicine 1991; (3): 25.

  • 9.     Peng Xiang, et al., Treatment of 24 cases of primary thrombocytopenic purpura with Shenqi Sanhuang Tang, Journal of Norman Bethune University of Medical Sciences 1989; 15(5): 538-539.

  • 10.  He Guoxing and Wang Xiuhua, Treatment of 52 patients with thrombocytopenic purpura with Bushen Shenxue Tang, Shanxi Journal of Traditional Chinese Medicine 1991; 7(6): 23-24.

  • 11.  Zhang Gaochen and Mao Yuwen, Treatment of thrombocytopenia with Weixueling Gao, Jiangsu Journal of Traditional Chinese Medicine 1985; 6(7): 312-313, 315.

  • 12.  Li Zhiyuan, Treatment of 23 cases of primary thrombocytopenic purpura mainly by warming and tonifying the spleen and kidney, Hubei Journal of Traditional Chinese Medicine 1987; (3): 24-25.

  • 13.  Duan Yu, et al., Treatment of primary thrombocytopenic purpura by modified Minor Decoction of Bupleurum, Journal of Traditional Chinese Medicine 1995; 13(2): 96-98.

  • 14.  Xiang Renpu, Treatment of 26 cases of primary thrombopenic purpura by tonifying the kidney and activating the blood, Zhejiang Journal of Traditional Chinese Medicine 1988; 23(2): 79.

  • 15.  San Weisheng and Ren Qifang, Chronic idiopathic thrombocytopenic purpura: 46 cases with differentiation of symptom-sign complex, Journal of the American College of Traditional Chinese Medicine 1983; (2): 25-29.

  • 16.  Yang Jingming, et al., Invigorating qi and promoting blood circulation in the treatment of chronic idiopathic thrompocytopenic purpura, Chinese Journal of Integrated Traditional and Western Medicine 1996; 2(1): 12-14.

  • 17.  Shen Di, et al., Clinical observation on effect of Xiaoyu Zhixue Tablet on 104 patients with idiopathic multifocal bleeding and platelet aggregation defect, Chinese Journal of Integrated Traditional and Western Medicine, 1998; 4(4): 247-250.


May 2000





Create Date : 22 ตุลาคม 2549
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