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Dilemmas in herbal medicine: The clinician's viewpoint
Thrombosis Research (2005) 117, 103 — 111
intl.elsevierhealth.com/journals/thre
Dilemmas in herbal medicine: The clinician’s viewpoint Alison Lee Private Practice, Walled Lake, MI, United States Received 19 April 2005; received in revised form 19 April 2005; accepted 4 May 2005 Available online 27 June 2005
The viewpoint of this discussion is based on 10 years of practice in an integrated Chinese medicine— Western medicine practice. I will discuss practicalities of treating patients who are either unwilling to use, unresponsive to, or seek to supplement conventional therapies. I will provide a rationale for using certain techniques for which there are limited available research sources to serve as a basis for use. I use a case presentation to discuss risk of complications resulting from potential anticoagulant effects of supplements. During the talk, I will also describe some insights into how herbal constituents may be useful in a wide variety of medical conditions. This is especially relevant now that it is understood how many conditions share a component of inflammation as part of pathophysiology [1]. My practice combines my conventional medical background with one of the oldest forms of medicine in the world, Chinese medicine. In this country, such a practice is considered unusual. In China, however, hospitals routinely combine contemporary Western treatment modalities with acupuncture and herbal therapy. When I studied
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in China in 1998, I stated to Dr. Ping Liang, head of Beijing Hospital’s acupuncture clinic, that mixing Eastern and Western medicine was considered unique, she laughed and answered, bOf course you need both Eastern and Western medicine together, just as you need two chopsticks to eat your mealQ. There exist many hospitals devoted primarily to traditional Chinese medicine, in which there exist conventional western medical departments. Western-style hospitals house departments of Acupuncture and Herbal Medicine. Patients are referred freely back and forth between departments. In China, professional practice of herbal medicine is considered a medical subspecialty. In a system similar to ours, patients seeking treatment of various ailments have access to simple herbal formulas through pharmacies, although often treatment may come from their grandmothers. In the case of a more significant medical condition requiring a complex herbal formula, treatment is available at the hospitals from a physician subspecialist in herbal medicine. In this system, patients are monitored on a regular basis, just as we monitor patients on pharmaceuticals, by a practitioner with full access to their entire medical record.
0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2005.05.003
104 My decision to incorporate herbal products into my practice is the outcome of a personal journey rather than a response to medical training. The practice I developed after my career as a pain medicine-trained anesthesiologist focused on acupuncture. In my practice, the role of herbal medicine is to serve as an adjunct in order to enhance the effects of acupuncture and facilitate decrease in the frequency, or total number, of treatments. There are both particular problems and insights related to the practice of Chinese herbal medicine. All of the concerns presented in other lectures of the conference apply in the context of Chinese herbal medicine. To add to the complexity of herbal medicine, Chinese formulas typically contain ten or more combined ingredients. These ingredients are selected based on features not well understood by most western medical practitioners [2]. Combination formulas present increased potential for interaction between the herbs themselves, and herbs and drugs. It is difficult to assess the research status of herbs and formulas because little Chinese scientific work is translated into English. It may not be clear, based on classical terminology used to describe herb or formula characteristics, what particular risks may be, or how to monitor patients for adverse effects. Yet all of these complexities also provide us with much to learn. It is a priority to be vigilant for risk factors and interactions, and at the same time, working with these agents day to day, it is interesting to speculate which ones warrant closer examination. Which ones might become the drugs of the 21st century? It felt like a great leap to consider adding herbal products to my practice after the acupuncture part of it was well established and successful. Despite the new-type qualities others attributed to my practice, at heart I was still a skeptical anesthesiologist. I felt much closer to the sterile rigor of the operating room than to the vagaries of nature. Plants were something that made your food taste better, made you vomit like the cat who ate the Christmas tree, or killed you. Plants came from the dirt. In contrast, everything in the operating room was prepared according to stringent standards and dose with microgram precision. In the operating room, as in the rest of medicine, practitioners expect intimate familiarity with medications, including details of pharmacology and interaction potential. In pursuit of the same level of knowledge of herbal preparations, I moved beyond medicine and pharmacology, to the field of pharmacognosy, which is the study of the natural origin of pharmaceuticals. The information I sought
A. Lee was scant, however there were many insights about my anesthesiology practice. Virtually all of the agents that were commonplace in the operating room: the depolarizing muscle relaxant succinylcholine, the nondepolarizing curariform muscle relaxants, resuscitation drugs ephedrine and atropine, digoxin, steroids, antibiotics, and opiates, all have their origins from natural products. The muscle relaxants originated as plant and frog derived arrow poisons of South American Indians [3]. Ephedrine derived from the ephedra plant [4], and atropine from belladonna [5]. Digoxin is one of a number of active compounds originating from foxglove [6]. The medical world is not as distant from the natural world, as I once thought. 25% of all pharmaceuticals contain plant-derived active compounds, and another 50% are structurally based on natural compounds [7]. In fact, the pharmaceutical industry exists today, thanks to plants. About 2000 years before Hippocrates, Egyptian papyrus describes the clinical use of willow bark, a potent source of salicylic acid. It was Hoffman’s acetylation of this product in 1897 that eventually propelled Bayer from its status as a struggling fabric dye company, to a successful creator and purveyor of proprietary compounds. Creating drugs from dye by-products was a tough business, but acetylsalicylic acid, with its deliberately catchy name, Aspirin, brought the advent of the pharmaceutical industry [8]. Salicylic acid is a substance of defense. It is present not only in willow bark but also in most plants including fruits and vegetables. When subjected to attack by bacteria or a virus, salicylic acid-producing plants increase production. This triggers DNA and RNA to produce defensive proteins. Apoptosis is triggered, ideally to cause the diseased area, such a leaf, to fall off and thereby spare the rest of the plant from disease [9]. The next chapter in the herb-coagulation story takes place in the early 1900s. Dogs ingested Melilotus alba, a member of the Fabiaciae family commonly known as sweet white clover, and developed hemorrhagic disorders. The cause of the bleeding was traced to coumarins contained in the plants. Another species, Melilotis officianalis, or yellow sweet clover, was planted in the Dakotas for cost-effective cattle feed that grew well in the poor soil. It is because of this plant that we have this conference. Hay was produced from the yellow sweet clover, and in the process, some spoiled. Cattle who ate the spoiled hay developed hemorrhagic disorders [10]. The causative agent was determined to dicumarol. In 1820, Vogel isolated 1,2-benzopyrone from Tonka bean and Melilotus officianalis (yellow sweet
Dilemmas in herbal medicine: The clinician’s viewpoint clover) [11]. The molecule was named coumarin, for the native French Guinea name of the tonka bean tree, bkumaruQ. Since then, over 1000 coumarin derivatives have been described, having been isolated from over 800 species of plants and microorganisms. Plant species containing coumarins are shown in Fig. 1 [12]. Coumarins have been well studied, and are recognized for modulating growth, germination, and, like salicylic acid, defense mechanisms in plants. In its scientific history, coumarins have been much considered for their potential in treating inflammation, infection, tumors, and modulating immunity. Responsible for the scent of hay or fresh-mown grass, coumarins have been used as flavorings and perfuming agents. Anticoagulation effects have been only one of many effects of this class of molecule [13,14]. As defense agents, coumarins repel insects, and form as a response to traumatic injuries, during the wilting process, drying, or as a result of plant diseases including viral or bacterial infection [15]. One of the more notorious members of the coumarin family is aflatoxin, a highly toxic metabolite of Aspergillus species. Aflatoxin B1 is best known for its association with hepatocellular carcinoma, in parts of the world with high consumption of moldy grains and legumes [16,17]. The molding process of the hay triggered increased in dicourmerol (3-3V-methylenebis(4-hydroxycoumarin)) production. This molecule was among 100 4-hydroxycoumarins studied by Karl Link in 1939 at the Wisconsin Alumni Research Foundation. This group determined that minimal structural requirements for anticoagulant activity were an intact 4hydroxycoumarin residue, with a 3-position substitution by a carbon chain, or unsubstituted. It was in this lab that Ilkawa synthesized Warfarin, which was named for the institution holding the patent,
Figure 1 Plant families with coumarin-containing species. *Reproduced with permission from [12].
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using the initials WARF as an acronym for the first part of the name. The end of the word derives from coumarin [18]. Warfarin gained fame as the world’s number one rodenticide, until 1951, when a military recruit ingested some in a suicide attempt. He was unsuccessful. In monitoring his recovery, a drug was born. Warfarin found use in the treatment of thromboembolic disorders and became one of the world’s most widely used anticoagulants [19]. Later in the discussion, I will return to the subject of the other, less clinically known, effects of the coumarins. In addition to providing much of today’s pharmaceutical armamentarium, herbs are the mainstay of the Chinese Medicine pharmacopoeia. Bear in mind, however, that although most Chinese medicines are plant-based, other types of products are used as well [20]. Many of these agents need to be looked at more closely in order to determine the extent of possible anticoagulant, antiplatelet, and prothrombotic effects [21]. In considering the vast array of substances to consider, I will reiterate that it is often difficult to sort out what products have research behind them, as opposed to reputation. The most well known product, however, is also well known in western science. This is the leech, from which hirudin is obtained. The leech actually contains a fascinating combination of compounds, enabling it to anesthetize its unsuspecting target, create bleeding in order to feed, and then seal the donor up again, perhaps to save more blood for another day [22]. Lesser known and less well studied is clinical use of snake products. Bungarus parvis, containing anticoagulant compounds, is used in the treatment of phlebitis and Raynaud’s syndrome [23]. Other, less understood agents include the wingless cockroach. Like the leech, it contains both prothrombotic and anticoagulant agents, and it has been used for gynecologic disorders, especially problems related to retained placenta, as well as coronary artery disease, and the treatment of wounds [24]. This coexistence of compounds with opposite effects demonstrates that a single product can have different effects. Many factors may determine which is predominant: dose, specifics of harvest, method of preparation, patient condition. In Chinese medicine, where herbs and other products are most often combined, other products in a formula may be used to bring out one property versus another. The same agent, therefore, may be used in a variety of clinical settings. This is one aspect of Chinese medicine that challenges the western medical model, where the same drug is generally used for the same or similar purpose, from patient
106 to patient [25]. In Western medicine, we may use gabapentin for pain or for seizures [26], but understanding this is probably an easier jump for a practitioner to make, than in the case of a Chinese herb such as angelica, which can be used in disorders with no clear pathophysiologic relationship, such as both menstrual disturbances, and migraine, for example [27]. To return to the topic of single agents of interest, Cuttlefish bone has been used primarily for treating gastrointestinal bleeding. The only compound to be identified is calcium, which has not been shown to have any effects on coagulation; obviously more study of effect, and then active agent, is warranted [28]. Squirrel feces, with prothrombotic activity, have been used in the treatment of snakebite [29]. Human hair, following a charring process believed to be necessary to create prothrombotic properties, has been used in the treatment of disorders associated with bleeding, both taken internally, and applied topically to injuries [30]. Given the strong record of historical use of Chinese medicine, partnered with the dearth of data of the type to which physicians have grown accustomed to demanding, how can herbal therapies be incorporated into practice? The rationale in my case was that, as an acupuncturist, I was experienced working with the pattern-based method of patient analysis that is also used in Chinese herbal medicine [31]. I had learned, through experience, that the observations of Chinese medicine’s ancient forefathers have contemporary clinical utility. Dr. DeSmet has spoken of the problems of making conclusions about safety and effectiveness when viewing extensive historical usage of herbs by ancient cultures. It is useful to keep these cautions in mind, and to apply clinical judgment as well. It was simpler to begin incorporating Western herbs into practice. Some of these have an evidence basis which is as strong as that standing behind many other commonly used therapies. Using Western products such as Ginkgo biloba, St. John’s Wort, and Glucosamine Sulfate is very much diagnosis-oriented herbal medicine, much like conventional pharmaceutical therapy; diagnosis: migraine, treatment: generic, or diagnosis: migraine, treatment: feverfew [32]. An additional level of comfort is provided, in the case of Western herbs, by the availability of standardized extracts. Herbs are available in many forms, including teas, and less expensive nonstandardized formulations; however, while standardization does not provide any assurance regarding presence of active ingredients, it makes a state-
A. Lee ment about product quality by indicating a known level of marker compound [33]. The issue of assuring product quality is an important one separate from the concerns of this conference. To return to the subject of the pattern oriented quality of Chinese diagnosis, Dr. Liang in China said, bMany symptoms, one disease, one symptom, many diseasesQ. Consider the first part of this statement: This is an ancient saying, and now we understand pleiotropic genes, where a single mutant gene produces apparently unrelated multiple effects. We have epidemiologic evidence that seemingly unrelated conditions and disorders can be associated. Long before contemporary medical literature described and elaborated on it, Chinese medicine described a relationship between gum disease and heart disease. Now, science has traced the cause to bacterial sources and related inflammatory changes: research reveals that two conditions long believed to be separate, actually share common pathophysiology. Seemingly disparate conditions are actually closely tied [34,35]. In the case of the latter part of the statement, one symptom, many diseases, according to the Chinese medical viewpoint, different patients who have migraine headaches require different treatment approaches. The tremulous nervous jittery patient with a migraine headache will require a regimen quite different from that administered to the overweight patient with irritable bowel and sinus problems who also has migraine headaches [36]. It is combination formulas that allow the physician to tailor treatments to patients with differing characteristics. Combination formulas can be created in a number of ways. In the process of incorporating these formulas into my treatment regimens, I underwent mentoring of several years duration with two Chinese trained physicians with extensive backgrounds in herbal medicine. At that time, about 10 years ago, I felt the safest choice was to offer custom herbal formulas compounded from bulk herbs. I was unable to get reliable details on the quality of bottled Chinese herbal products. While there are still many drawbacks to relying on visual inspection to identify herbs, the Chinese herb industry relies on this, as do practitioners [37]. Rather than trust a company of which I had no knowledge, I asked my two mentors to examine the bulk products independently, and separately concur on correct identity, proper plant part, and level of quality. In order to limit as much as possible herb misidentification, I chose to limit my formulary to plants with fairly characteristic appearances and no other herbs closely resembling them, as problems related to
Dilemmas in herbal medicine: The clinician’s viewpoint Aristolochic acid stemmed from herb misidentification [38]. Leaves and roots and barks were mixed into daily dosage bags, to be decocted by patients at home into smelly brews, and drunk several times a day. This method of administration is inconvenient, but it assures practitioner knowledge of ingredients, and offers the most flexibility for individualization of treatments and subtle modifications depending on patient response. It is in these combinations that both the problems and the promise of Chinese herbal medicine arise. As concerned as we are about adverse reactions to polypharmacy in conventional medical practice, consider the additional unknowns when patients are receiving formulas containing ten or more herbs. But the combination formulas also allow for the idea of the synergistic effects between the herbs. Although this has not been well studied, it is theorized that patients receive lower doses of each herb when they are expertly combined. In this way, the total dose of each herb is reduced, which is purported to reduce side effects. Another way that combination formulas are felt to reduce side effects is to use herbs which directly counter known adverse effects of others. In the case of a formula that contains many herbs, for example, which benefit fatigue, but are gastrointestinal irritants, the physician formulating the combination will add herbs to counter the undesired effect [39]. A more convenient way of administering combination formulas is to use what are referred to as bpatent formulasQ. These are bottled pills comprised of a combination of herbs. Although much individualization is done in Chinese medicine, there are numerous basic patterns, and these formulas can be used in a great many cases. Sometimes two such patents are combined for further individualization [40]. The term patent formula is a misnomer because in Chinese medicine there is no patent process for formulations. The formulas are protected through secrecy. There is no requirement for ingredient disclosure. This leads to problems with quality control. In addition to this problem with some legitimately imported products, it has also proven difficult to prevent counterfeit or smuggled products from reaching the market in this country [41]. There are case reports of patients obtaining herbal products whose unknown contents turned out be pharmaceuticals, including ones capable of increasing the effects of anticoagulant therapy, namely phenylbutazone [42], and steroids [43]. I started my practice in the wake of the creation of DSHEA. Companies are now more responsive to
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demands for quality assurance. Many US companies are producing Chinese formulas, and some factories in China disclose ingredients and adhere to GMP production standards of Australia or Europe [44]. At present, although DSHEA provides for establishing GMP guidelines for dietary supplements, the process is not complete at this time [45]. Even when manufacturing processes meet international GMP standards, I do not know of any makers of Chinese herbal formulas who include standardization procedures in their production. The historical basis of Chinese medical practice has not accounted for the vast variability of plant characteristics. Reliable companies must include screens for pesticides and heavy metals on specimens directed for use in commercial products [46]. Furthermore, considering the implications of diseased plants, and their potentially increased levels of salicylate or anticoagulant coumarins, bacterial and viral assays should be performed. In deciding what companies to recommend to your patients, reputable ones will provide results of such testing of their raw materials. When patients receive herbs in a medical practice, it’s a different situation from the way most herbs are administered. As studies continue to verify, it is common for people to select and purchase herbs and other nutraceutical products without consulting a medical professional [47]. By the time I have seen most patients, they have often been to the health food store, or supplement aisle of their supermarket or pharmacy, taking advantage of the tremendous access to supplements that is being discussed at this conference. People generally seem quite willing to accept supplement recommendations from people whose qualifications are unknown. In today’s pressured, often impersonal medical environment, the recommendations of a friendly, attentive sales person may carry a lot of weight. Behind this is the common perception that if products are natural, they are harmless. One of the factors that has driven the success of my practice is that I offer alternatives to pharmaceutical treatments for several common conditions, including pain, depression, gastrointestinal complaints, and menopause. Many patients have told me, bI’m here because I don’t want drugsQ. They state numerous reasons: insufficient evidence that medication will treat their complaint, unwillingness to accept the risk of side effects, or they are working on simplifying a complicated drug regimen. They go on and say, bI don’t want chemicals in my body, but I’ll take herbsQ. Often people fail to make the connection
108 between herbs, and pharmaceutical effects, or potential adverse effects. I will present a case example of the road traveled by a typical patient in my practice. For simplicity and teaching purposes, I have altered her course of events slightly. The patient is 49-year-old woman who first consulted me 7 years ago after her youngest child left home. She was 42 years old and attending a prestigious, high-pressure law school. She had migraine headaches well managed on Imitrex, but she had just been diagnosed with hypertension and wished to treat the migraines with acupuncture and discontinue the Imitrex. While my practice emphasizes acupuncture, I also suggested a program for stress management, and made dietary recommendations. At the time, I was particularly interested in the relationship between pain and inflammation, as well as the concept that a low level of inflammation was endemic, and contributory to many disease processes, including migraine [48]. I recommended Omega-3 fatty acid supplementation with fish oil, accompanied by Vitamin E [49,50]. Vitamin E was added to enhance stability and maximize activity of the fish oil [51,52]. The patient responded well to a course of acupuncture treatment, and returned periodically for maintenance visits, as is customary in the treatment of chronic conditions with acupuncture. In the case of this patient, she returned a few times a year. At one point she mentioned that she was migraine free except for the circumstances in which she experienced a combination of stressors all at once: being pre-menstrual, preparing for an exam, and arguing with her husband. The patient was treated with a bulk herbal formula to prepare as a decoction, to use if she was scheduled to take an exam the week before her period, in case she had a fight with her husband. She was satisfied with the results, completed law school, and decreased her maintenance visits to one per year. At the time of her next visit, she was continuing the fish oil with its anti-platelet effects, the Vitamin E with the same [53,54]. She reported that she had seen her primary physician because bI am just not feeling like myself these daysQ. Her menstrual cycles had shortened, she had cold hands and feet, she was not sleeping well and was feeling forgetful and depressed. The primary physician identified no abnormalities. After a discussion of the risks and benefits, the patient declined hormone replacement therapy. She also stated work demands rendered her unable to come in very often, and she requested an herbal recommendation rather than a series of acupuncture treatments.
A. Lee I recommended Ginkgo biloba, which has some evidence to suggest benefit in depression and cognitive disturbance when associated with sleep disturbance [55], and might provide a sense of increased circulation [56]. The simplicity of the idea appealed to the patient and she agreed to a 3month trial. Because of contradictory conclusions regarding the effect of Ginkgo on platelet function, I cautioned her to reduce the fish oil and Vitamin E. I have had two patients in my practice develop epistaxis while on this combination. While there were confounding factors for both, neither demonstrated abnormal coagulation studies, and there is evidence that whether or not ginkgo affects coagulation, routine indices do not reflect any disturbance [57,58]. Between this visit and the next, the patient developed hot flashes. Amid the possible remedies at the health food store, she selected red clover. A member of the Leguminosae family, red clover contains coumarins [59]. Unaware, this patient may have just added another anticoagulant to her regimen. Over the next few months, she is busy with work. She is feeling low in energy, she is not exercising, she is gaining weight, she thinks her complexion has developed a pallor. Again, evaluation by her primary care physician is negative. One night, on the Internet, she comes across a Chinese medicine site featuring a pretty bottle containing a formula referred to as Women’s Precious. Often the Chinese names are translated to musical, flowery names. Alternative names for the formula include Eight Treasure Decoction, although there are others. This is a formula commonly used to treat certain menstrual or menopausal disturbances, often when associated with fatigue. The site included a list of complaints for which the formula might be indicated, which led this patient to believe the formula might be helpful. When she reviewed the ingredient list, she noted that many of those listed were also in the tea she had gotten from me when she first presented to my office. She was not aware that the doses and combinations could change their effects. Nor did she understand that at least two of the components, angelica and ligusticum, contain coumarins and ligustilide, respectively, with potential anticoagulant effects [60,61]. It is notable that when combination formulas contain herbs which may decrease coagulation, they also contain prothrombotic herbs. This is the case with Women’s Precious [62]. Another aspect of anticoagulant herbs is that many of them also contain prothrombotic compounds. The leech is the best known example. As I have discussed, the coumarins are a complex lot, and they are only
Dilemmas in herbal medicine: The clinician’s viewpoint one compound present in the plants from which they have been isolated. Coumarins provide us with aflatoxin, yet they also show anti-neoplastic activity. Might it be that plants containing anticoagulant coumarins also contain compounds supporting coagulation? Depending on the dose or other conditions, one effect or another may predominate, in a way similar to the biphasic response to dopamine depending on whether the dose is low or high [63]. This is discussed further in the review of research priorities, which will be presented tomorrow. We have limited access to Chinese medical literature which may discuss safety of herbal medicine. It is clear, however, that potent Chinese medicines were not meant to be used in a medically unmonitored setting. They were meant to be used in combination with numerous other products such as this patient, and many others, have done [64]. The next stage of this patient’s story happens shortly before this meeting. She reads in the newspaper about a report that women in her age range who experience from migraines with aura are at increased risk for stroke [65]. She ponders whether she should add aspirin to her regimen. Fortunately it is time for her yearly visit with me, and holds the question for her appointment. In the case of older patients, there is additional risk for complications. All the considerations that have been reviewed in the previous case apply. In addition, older patients are often on multiple medications. They may have hepatic or renal insufficiency, with decreased excretion of active principles, and possible buildup of active metabolites. These possibilities are largely cause for speculation, since pharmacologic and pharmacokinetic characteristics of herbs and supplements are not well defined. Furthermore, the elderly have increased vascular fragility, predisposing them to bleeding, and impairment of balance which contributes to falls and injury [66]. And finally, from what I have seen, there is usually somebody, somewhere in their life eager to help, who brings them a product recommendation. . . or two. In most cases, when I see complex or elderly patients who request a treatment regimen, my intervention centers or reducing what they are taking, rather than giving something. Most commonly, when they present at the time of the first visit with their shopping bag full of bottles, I prune their program. In addition to looking behind me to see what problems are lurking, I also look forward to see what lessons herbs can teach us about how to treat disease. When I first began studying herbs as I described at the start of the talk, I was a bit skeptical as I read about studies done in China
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which elucidated numerous diverse effects. It seemed that for plant after plant, isolates demonstrated effects that were immune-enhancing, anti-inflammatory, and anti-cancer. Today we are seeing evidence that inflammation has a close tie to cardiovascular disease and cancer, among other conditions [67,68]. It is also now understood that inflammation and hypercoagulability are also closely related [69], especially but not exclusively in the hypercoagulable state of malignancy. It has been suggested that in seeking better treatments for the hypercoagulable state of cancer, positive effects on tumor growth and dissemination may also be obtained [70]. Interestingly, there have been encouraging outcomes resulting from examination of treatment of malignancy with coumarins, including warfarin [71]. As a clinician I am obligated to consider patient safety, yet I have also taken on the task of treating patients who consider what I offer to be a last resort. In this capacity, I propose the question: how can we use natural products, or natural product constituents, with their seemingly, but not truly diverse effects, to improve treatment of many of today’s difficult diseases, including thromboembolic conditions?
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[36] Peilin S. Treatment of pain with Chinese herbs and acupuncture. Edinburgh7 Churchill Livingston; 2004. p. 175 – 95. [37] Chen MX. Study on white light diffuse reflection spectrum of Chinese herbal medicine. Guang Pu Xue Yu Guang Pu Fen XI 2004;24(6):655 – 8. [38] Vanherweghem LJ. Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs neuropathy). J Altern Complement Med 1998;4(1): 9 – 13. [39] Bensky D, Barolet R. Chinese herbal medicine formulas and strategies. Eastland Press; 1990. [40] Taylor M. Chinese patent medicines. Global Eyes International Press; 1998. p. 33 – 42. [41] Taylor M. Chinese Patent Medicines. Global Eyes International Press; 1998. p. 42, 51. [42] Ries CA, Sahud MA. Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 1975;231:352 – 5. [43] Edwards CJ, Lian TY, Chng HH. Cushing’s syndrome caused by treatment of gout with traditional Chinese medicine. QJ Med 2002;95:705. [44] Taylor M. Chinese Patent Medicines. Global Eyes International Press; 1998. p. 42, 51. [45] FDA website: http://www.cfsan.fda.gov/~dms/dietsupp. html. [46] Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM, Davis RB, et al. Heavy metal content of ayurvedic herbal medicine products. JAMA 2004;292:2868 – 73. [47] Kessler RC, Davis RB, Foster DF, Van Rompay MI, Walters EE, Wilkey SA, et al. Long-term trends in the use of complementary and alternative medicine therapies in the United States. Ann Intern Med 2001;21;135 (4):262 – 8. [48] Parantainen J, Vapatalo H, Hokkanen E. Relevance of prostaglandins in migraine. Cephalalgia 1985;2(5 Suppl.): 93 – 7. [49] Rakel DP, Rindfleisch A. Inflammation: nutritional, botanical, and mind—body influences. South Med J 2005;98(3): 303 – 10. [50] Smith WL. Cyclooxygenases, peroxide tone and the allure of fish oil. Curr Opin Cell Biol 2005;17(2):174 – 82. [51] Tsuzuki T, Igarashi M, Iwata T, Yamauchi-Sato Y, Yamamoti T, Ogita K, et al. Oxidation rate of conjugated linoleic acid and conjugated linolenic acid is slowed by triacylglycerol esterification and alpha-tocopherol. Lipids 2004;39(5): 475 – 80. [52] Saito M. Dietary docosahexaenoic acid does not promote tissue lipid peroxide formation to the extent expected from the peroxidizability index of the lipids. Biofactors 2000;123(1—4):15 – 24. [53] Celestini A, Pulcinelli FM, Pignatelli P, Lenti L, Frati G, Gazzaniga PP, et al. Vitamin E potentiates the antiplatelet activity of aspirin in collagen-stimulated platelets. Haematologica 2002;87(4):420 – 6. [54] Parent CA, Lagarde M, Venton DL, Le Breton GC. Selective modulation of the human platelet thromboxane A2/prostaglandin H2 receptor by eicosapentaenoic and docosahexaenoic acids in intact platelets and solubilized platelet membranes. J Biol Chem 1992;267(10):6541 – 7. [55] Hemmeter U, Annen B, Bischof R, Bruderlin U, Hatzinger U, Rose U, et al. Polysomnographic effects of adjuvant Ginkgo biloba therapy in patients with major depression medicated with trimipramine. Pharmacopsychiatry 2001; 34(2):50 – 9. [56] Mehlsen J, Drabaek H, Wiinberg N, Winther K. Effects of a Ginkgo biloba extract on forearm haemodynamics in
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[65] Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Migraine, headache, and the risk of stroke in women, a prospective study. Neurology 2005;22;64(6):1020 – 6. [66] Williams BR, Kim J. Medication use and prescribing considerations for elderly patients. Dent Clin North Am 2005;49(2):411 – 27. [67] Van Oostrom AJ, van Wijk J, Capezas MC. Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis. Drugs 2004;64(Suppl. 2):19 – 41. [68] Nishimura F, Soga Y, Iwamoto Y, Kudo C, Murayama Y. Periodontal disease as part of the insulin resistance syndrome in diabetic patients. J Int Acad Periodontol 2005;7(1):16 – 20. [69] Van de Wouwer M, Collen D, Conway EM. Thrombomodulinprotein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24(8):1374 – 83. [70] Caine GJ, Stonelake PS, Lip GY, Kehoe ST. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia 2002;4(6):465 – 73. [71] Thornes RD. Clinical and biological observations associated with coumarins. In: O’Kennedy R, Thornes RD, editors. Coumarins—Biology, Applications and Mode of Action. Chichester-New York: John Wiley and Sons; 1997. p. 242—51, 255.
intl.elsevierhealth.com/journals/thre
Dilemmas in herbal medicine: The clinician’s viewpoint Alison Lee Private Practice, Walled Lake, MI, United States Received 19 April 2005; received in revised form 19 April 2005; accepted 4 May 2005 Available online 27 June 2005
The viewpoint of this discussion is based on 10 years of practice in an integrated Chinese medicine— Western medicine practice. I will discuss practicalities of treating patients who are either unwilling to use, unresponsive to, or seek to supplement conventional therapies. I will provide a rationale for using certain techniques for which there are limited available research sources to serve as a basis for use. I use a case presentation to discuss risk of complications resulting from potential anticoagulant effects of supplements. During the talk, I will also describe some insights into how herbal constituents may be useful in a wide variety of medical conditions. This is especially relevant now that it is understood how many conditions share a component of inflammation as part of pathophysiology [1]. My practice combines my conventional medical background with one of the oldest forms of medicine in the world, Chinese medicine. In this country, such a practice is considered unusual. In China, however, hospitals routinely combine contemporary Western treatment modalities with acupuncture and herbal therapy. When I studied
E-mail address: [email protected].
in China in 1998, I stated to Dr. Ping Liang, head of Beijing Hospital’s acupuncture clinic, that mixing Eastern and Western medicine was considered unique, she laughed and answered, bOf course you need both Eastern and Western medicine together, just as you need two chopsticks to eat your mealQ. There exist many hospitals devoted primarily to traditional Chinese medicine, in which there exist conventional western medical departments. Western-style hospitals house departments of Acupuncture and Herbal Medicine. Patients are referred freely back and forth between departments. In China, professional practice of herbal medicine is considered a medical subspecialty. In a system similar to ours, patients seeking treatment of various ailments have access to simple herbal formulas through pharmacies, although often treatment may come from their grandmothers. In the case of a more significant medical condition requiring a complex herbal formula, treatment is available at the hospitals from a physician subspecialist in herbal medicine. In this system, patients are monitored on a regular basis, just as we monitor patients on pharmaceuticals, by a practitioner with full access to their entire medical record.
0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2005.05.003
104 My decision to incorporate herbal products into my practice is the outcome of a personal journey rather than a response to medical training. The practice I developed after my career as a pain medicine-trained anesthesiologist focused on acupuncture. In my practice, the role of herbal medicine is to serve as an adjunct in order to enhance the effects of acupuncture and facilitate decrease in the frequency, or total number, of treatments. There are both particular problems and insights related to the practice of Chinese herbal medicine. All of the concerns presented in other lectures of the conference apply in the context of Chinese herbal medicine. To add to the complexity of herbal medicine, Chinese formulas typically contain ten or more combined ingredients. These ingredients are selected based on features not well understood by most western medical practitioners [2]. Combination formulas present increased potential for interaction between the herbs themselves, and herbs and drugs. It is difficult to assess the research status of herbs and formulas because little Chinese scientific work is translated into English. It may not be clear, based on classical terminology used to describe herb or formula characteristics, what particular risks may be, or how to monitor patients for adverse effects. Yet all of these complexities also provide us with much to learn. It is a priority to be vigilant for risk factors and interactions, and at the same time, working with these agents day to day, it is interesting to speculate which ones warrant closer examination. Which ones might become the drugs of the 21st century? It felt like a great leap to consider adding herbal products to my practice after the acupuncture part of it was well established and successful. Despite the new-type qualities others attributed to my practice, at heart I was still a skeptical anesthesiologist. I felt much closer to the sterile rigor of the operating room than to the vagaries of nature. Plants were something that made your food taste better, made you vomit like the cat who ate the Christmas tree, or killed you. Plants came from the dirt. In contrast, everything in the operating room was prepared according to stringent standards and dose with microgram precision. In the operating room, as in the rest of medicine, practitioners expect intimate familiarity with medications, including details of pharmacology and interaction potential. In pursuit of the same level of knowledge of herbal preparations, I moved beyond medicine and pharmacology, to the field of pharmacognosy, which is the study of the natural origin of pharmaceuticals. The information I sought
A. Lee was scant, however there were many insights about my anesthesiology practice. Virtually all of the agents that were commonplace in the operating room: the depolarizing muscle relaxant succinylcholine, the nondepolarizing curariform muscle relaxants, resuscitation drugs ephedrine and atropine, digoxin, steroids, antibiotics, and opiates, all have their origins from natural products. The muscle relaxants originated as plant and frog derived arrow poisons of South American Indians [3]. Ephedrine derived from the ephedra plant [4], and atropine from belladonna [5]. Digoxin is one of a number of active compounds originating from foxglove [6]. The medical world is not as distant from the natural world, as I once thought. 25% of all pharmaceuticals contain plant-derived active compounds, and another 50% are structurally based on natural compounds [7]. In fact, the pharmaceutical industry exists today, thanks to plants. About 2000 years before Hippocrates, Egyptian papyrus describes the clinical use of willow bark, a potent source of salicylic acid. It was Hoffman’s acetylation of this product in 1897 that eventually propelled Bayer from its status as a struggling fabric dye company, to a successful creator and purveyor of proprietary compounds. Creating drugs from dye by-products was a tough business, but acetylsalicylic acid, with its deliberately catchy name, Aspirin, brought the advent of the pharmaceutical industry [8]. Salicylic acid is a substance of defense. It is present not only in willow bark but also in most plants including fruits and vegetables. When subjected to attack by bacteria or a virus, salicylic acid-producing plants increase production. This triggers DNA and RNA to produce defensive proteins. Apoptosis is triggered, ideally to cause the diseased area, such a leaf, to fall off and thereby spare the rest of the plant from disease [9]. The next chapter in the herb-coagulation story takes place in the early 1900s. Dogs ingested Melilotus alba, a member of the Fabiaciae family commonly known as sweet white clover, and developed hemorrhagic disorders. The cause of the bleeding was traced to coumarins contained in the plants. Another species, Melilotis officianalis, or yellow sweet clover, was planted in the Dakotas for cost-effective cattle feed that grew well in the poor soil. It is because of this plant that we have this conference. Hay was produced from the yellow sweet clover, and in the process, some spoiled. Cattle who ate the spoiled hay developed hemorrhagic disorders [10]. The causative agent was determined to dicumarol. In 1820, Vogel isolated 1,2-benzopyrone from Tonka bean and Melilotus officianalis (yellow sweet
Dilemmas in herbal medicine: The clinician’s viewpoint clover) [11]. The molecule was named coumarin, for the native French Guinea name of the tonka bean tree, bkumaruQ. Since then, over 1000 coumarin derivatives have been described, having been isolated from over 800 species of plants and microorganisms. Plant species containing coumarins are shown in Fig. 1 [12]. Coumarins have been well studied, and are recognized for modulating growth, germination, and, like salicylic acid, defense mechanisms in plants. In its scientific history, coumarins have been much considered for their potential in treating inflammation, infection, tumors, and modulating immunity. Responsible for the scent of hay or fresh-mown grass, coumarins have been used as flavorings and perfuming agents. Anticoagulation effects have been only one of many effects of this class of molecule [13,14]. As defense agents, coumarins repel insects, and form as a response to traumatic injuries, during the wilting process, drying, or as a result of plant diseases including viral or bacterial infection [15]. One of the more notorious members of the coumarin family is aflatoxin, a highly toxic metabolite of Aspergillus species. Aflatoxin B1 is best known for its association with hepatocellular carcinoma, in parts of the world with high consumption of moldy grains and legumes [16,17]. The molding process of the hay triggered increased in dicourmerol (3-3V-methylenebis(4-hydroxycoumarin)) production. This molecule was among 100 4-hydroxycoumarins studied by Karl Link in 1939 at the Wisconsin Alumni Research Foundation. This group determined that minimal structural requirements for anticoagulant activity were an intact 4hydroxycoumarin residue, with a 3-position substitution by a carbon chain, or unsubstituted. It was in this lab that Ilkawa synthesized Warfarin, which was named for the institution holding the patent,
Figure 1 Plant families with coumarin-containing species. *Reproduced with permission from [12].
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using the initials WARF as an acronym for the first part of the name. The end of the word derives from coumarin [18]. Warfarin gained fame as the world’s number one rodenticide, until 1951, when a military recruit ingested some in a suicide attempt. He was unsuccessful. In monitoring his recovery, a drug was born. Warfarin found use in the treatment of thromboembolic disorders and became one of the world’s most widely used anticoagulants [19]. Later in the discussion, I will return to the subject of the other, less clinically known, effects of the coumarins. In addition to providing much of today’s pharmaceutical armamentarium, herbs are the mainstay of the Chinese Medicine pharmacopoeia. Bear in mind, however, that although most Chinese medicines are plant-based, other types of products are used as well [20]. Many of these agents need to be looked at more closely in order to determine the extent of possible anticoagulant, antiplatelet, and prothrombotic effects [21]. In considering the vast array of substances to consider, I will reiterate that it is often difficult to sort out what products have research behind them, as opposed to reputation. The most well known product, however, is also well known in western science. This is the leech, from which hirudin is obtained. The leech actually contains a fascinating combination of compounds, enabling it to anesthetize its unsuspecting target, create bleeding in order to feed, and then seal the donor up again, perhaps to save more blood for another day [22]. Lesser known and less well studied is clinical use of snake products. Bungarus parvis, containing anticoagulant compounds, is used in the treatment of phlebitis and Raynaud’s syndrome [23]. Other, less understood agents include the wingless cockroach. Like the leech, it contains both prothrombotic and anticoagulant agents, and it has been used for gynecologic disorders, especially problems related to retained placenta, as well as coronary artery disease, and the treatment of wounds [24]. This coexistence of compounds with opposite effects demonstrates that a single product can have different effects. Many factors may determine which is predominant: dose, specifics of harvest, method of preparation, patient condition. In Chinese medicine, where herbs and other products are most often combined, other products in a formula may be used to bring out one property versus another. The same agent, therefore, may be used in a variety of clinical settings. This is one aspect of Chinese medicine that challenges the western medical model, where the same drug is generally used for the same or similar purpose, from patient
106 to patient [25]. In Western medicine, we may use gabapentin for pain or for seizures [26], but understanding this is probably an easier jump for a practitioner to make, than in the case of a Chinese herb such as angelica, which can be used in disorders with no clear pathophysiologic relationship, such as both menstrual disturbances, and migraine, for example [27]. To return to the topic of single agents of interest, Cuttlefish bone has been used primarily for treating gastrointestinal bleeding. The only compound to be identified is calcium, which has not been shown to have any effects on coagulation; obviously more study of effect, and then active agent, is warranted [28]. Squirrel feces, with prothrombotic activity, have been used in the treatment of snakebite [29]. Human hair, following a charring process believed to be necessary to create prothrombotic properties, has been used in the treatment of disorders associated with bleeding, both taken internally, and applied topically to injuries [30]. Given the strong record of historical use of Chinese medicine, partnered with the dearth of data of the type to which physicians have grown accustomed to demanding, how can herbal therapies be incorporated into practice? The rationale in my case was that, as an acupuncturist, I was experienced working with the pattern-based method of patient analysis that is also used in Chinese herbal medicine [31]. I had learned, through experience, that the observations of Chinese medicine’s ancient forefathers have contemporary clinical utility. Dr. DeSmet has spoken of the problems of making conclusions about safety and effectiveness when viewing extensive historical usage of herbs by ancient cultures. It is useful to keep these cautions in mind, and to apply clinical judgment as well. It was simpler to begin incorporating Western herbs into practice. Some of these have an evidence basis which is as strong as that standing behind many other commonly used therapies. Using Western products such as Ginkgo biloba, St. John’s Wort, and Glucosamine Sulfate is very much diagnosis-oriented herbal medicine, much like conventional pharmaceutical therapy; diagnosis: migraine, treatment: generic, or diagnosis: migraine, treatment: feverfew [32]. An additional level of comfort is provided, in the case of Western herbs, by the availability of standardized extracts. Herbs are available in many forms, including teas, and less expensive nonstandardized formulations; however, while standardization does not provide any assurance regarding presence of active ingredients, it makes a state-
A. Lee ment about product quality by indicating a known level of marker compound [33]. The issue of assuring product quality is an important one separate from the concerns of this conference. To return to the subject of the pattern oriented quality of Chinese diagnosis, Dr. Liang in China said, bMany symptoms, one disease, one symptom, many diseasesQ. Consider the first part of this statement: This is an ancient saying, and now we understand pleiotropic genes, where a single mutant gene produces apparently unrelated multiple effects. We have epidemiologic evidence that seemingly unrelated conditions and disorders can be associated. Long before contemporary medical literature described and elaborated on it, Chinese medicine described a relationship between gum disease and heart disease. Now, science has traced the cause to bacterial sources and related inflammatory changes: research reveals that two conditions long believed to be separate, actually share common pathophysiology. Seemingly disparate conditions are actually closely tied [34,35]. In the case of the latter part of the statement, one symptom, many diseases, according to the Chinese medical viewpoint, different patients who have migraine headaches require different treatment approaches. The tremulous nervous jittery patient with a migraine headache will require a regimen quite different from that administered to the overweight patient with irritable bowel and sinus problems who also has migraine headaches [36]. It is combination formulas that allow the physician to tailor treatments to patients with differing characteristics. Combination formulas can be created in a number of ways. In the process of incorporating these formulas into my treatment regimens, I underwent mentoring of several years duration with two Chinese trained physicians with extensive backgrounds in herbal medicine. At that time, about 10 years ago, I felt the safest choice was to offer custom herbal formulas compounded from bulk herbs. I was unable to get reliable details on the quality of bottled Chinese herbal products. While there are still many drawbacks to relying on visual inspection to identify herbs, the Chinese herb industry relies on this, as do practitioners [37]. Rather than trust a company of which I had no knowledge, I asked my two mentors to examine the bulk products independently, and separately concur on correct identity, proper plant part, and level of quality. In order to limit as much as possible herb misidentification, I chose to limit my formulary to plants with fairly characteristic appearances and no other herbs closely resembling them, as problems related to
Dilemmas in herbal medicine: The clinician’s viewpoint Aristolochic acid stemmed from herb misidentification [38]. Leaves and roots and barks were mixed into daily dosage bags, to be decocted by patients at home into smelly brews, and drunk several times a day. This method of administration is inconvenient, but it assures practitioner knowledge of ingredients, and offers the most flexibility for individualization of treatments and subtle modifications depending on patient response. It is in these combinations that both the problems and the promise of Chinese herbal medicine arise. As concerned as we are about adverse reactions to polypharmacy in conventional medical practice, consider the additional unknowns when patients are receiving formulas containing ten or more herbs. But the combination formulas also allow for the idea of the synergistic effects between the herbs. Although this has not been well studied, it is theorized that patients receive lower doses of each herb when they are expertly combined. In this way, the total dose of each herb is reduced, which is purported to reduce side effects. Another way that combination formulas are felt to reduce side effects is to use herbs which directly counter known adverse effects of others. In the case of a formula that contains many herbs, for example, which benefit fatigue, but are gastrointestinal irritants, the physician formulating the combination will add herbs to counter the undesired effect [39]. A more convenient way of administering combination formulas is to use what are referred to as bpatent formulasQ. These are bottled pills comprised of a combination of herbs. Although much individualization is done in Chinese medicine, there are numerous basic patterns, and these formulas can be used in a great many cases. Sometimes two such patents are combined for further individualization [40]. The term patent formula is a misnomer because in Chinese medicine there is no patent process for formulations. The formulas are protected through secrecy. There is no requirement for ingredient disclosure. This leads to problems with quality control. In addition to this problem with some legitimately imported products, it has also proven difficult to prevent counterfeit or smuggled products from reaching the market in this country [41]. There are case reports of patients obtaining herbal products whose unknown contents turned out be pharmaceuticals, including ones capable of increasing the effects of anticoagulant therapy, namely phenylbutazone [42], and steroids [43]. I started my practice in the wake of the creation of DSHEA. Companies are now more responsive to
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demands for quality assurance. Many US companies are producing Chinese formulas, and some factories in China disclose ingredients and adhere to GMP production standards of Australia or Europe [44]. At present, although DSHEA provides for establishing GMP guidelines for dietary supplements, the process is not complete at this time [45]. Even when manufacturing processes meet international GMP standards, I do not know of any makers of Chinese herbal formulas who include standardization procedures in their production. The historical basis of Chinese medical practice has not accounted for the vast variability of plant characteristics. Reliable companies must include screens for pesticides and heavy metals on specimens directed for use in commercial products [46]. Furthermore, considering the implications of diseased plants, and their potentially increased levels of salicylate or anticoagulant coumarins, bacterial and viral assays should be performed. In deciding what companies to recommend to your patients, reputable ones will provide results of such testing of their raw materials. When patients receive herbs in a medical practice, it’s a different situation from the way most herbs are administered. As studies continue to verify, it is common for people to select and purchase herbs and other nutraceutical products without consulting a medical professional [47]. By the time I have seen most patients, they have often been to the health food store, or supplement aisle of their supermarket or pharmacy, taking advantage of the tremendous access to supplements that is being discussed at this conference. People generally seem quite willing to accept supplement recommendations from people whose qualifications are unknown. In today’s pressured, often impersonal medical environment, the recommendations of a friendly, attentive sales person may carry a lot of weight. Behind this is the common perception that if products are natural, they are harmless. One of the factors that has driven the success of my practice is that I offer alternatives to pharmaceutical treatments for several common conditions, including pain, depression, gastrointestinal complaints, and menopause. Many patients have told me, bI’m here because I don’t want drugsQ. They state numerous reasons: insufficient evidence that medication will treat their complaint, unwillingness to accept the risk of side effects, or they are working on simplifying a complicated drug regimen. They go on and say, bI don’t want chemicals in my body, but I’ll take herbsQ. Often people fail to make the connection
108 between herbs, and pharmaceutical effects, or potential adverse effects. I will present a case example of the road traveled by a typical patient in my practice. For simplicity and teaching purposes, I have altered her course of events slightly. The patient is 49-year-old woman who first consulted me 7 years ago after her youngest child left home. She was 42 years old and attending a prestigious, high-pressure law school. She had migraine headaches well managed on Imitrex, but she had just been diagnosed with hypertension and wished to treat the migraines with acupuncture and discontinue the Imitrex. While my practice emphasizes acupuncture, I also suggested a program for stress management, and made dietary recommendations. At the time, I was particularly interested in the relationship between pain and inflammation, as well as the concept that a low level of inflammation was endemic, and contributory to many disease processes, including migraine [48]. I recommended Omega-3 fatty acid supplementation with fish oil, accompanied by Vitamin E [49,50]. Vitamin E was added to enhance stability and maximize activity of the fish oil [51,52]. The patient responded well to a course of acupuncture treatment, and returned periodically for maintenance visits, as is customary in the treatment of chronic conditions with acupuncture. In the case of this patient, she returned a few times a year. At one point she mentioned that she was migraine free except for the circumstances in which she experienced a combination of stressors all at once: being pre-menstrual, preparing for an exam, and arguing with her husband. The patient was treated with a bulk herbal formula to prepare as a decoction, to use if she was scheduled to take an exam the week before her period, in case she had a fight with her husband. She was satisfied with the results, completed law school, and decreased her maintenance visits to one per year. At the time of her next visit, she was continuing the fish oil with its anti-platelet effects, the Vitamin E with the same [53,54]. She reported that she had seen her primary physician because bI am just not feeling like myself these daysQ. Her menstrual cycles had shortened, she had cold hands and feet, she was not sleeping well and was feeling forgetful and depressed. The primary physician identified no abnormalities. After a discussion of the risks and benefits, the patient declined hormone replacement therapy. She also stated work demands rendered her unable to come in very often, and she requested an herbal recommendation rather than a series of acupuncture treatments.
A. Lee I recommended Ginkgo biloba, which has some evidence to suggest benefit in depression and cognitive disturbance when associated with sleep disturbance [55], and might provide a sense of increased circulation [56]. The simplicity of the idea appealed to the patient and she agreed to a 3month trial. Because of contradictory conclusions regarding the effect of Ginkgo on platelet function, I cautioned her to reduce the fish oil and Vitamin E. I have had two patients in my practice develop epistaxis while on this combination. While there were confounding factors for both, neither demonstrated abnormal coagulation studies, and there is evidence that whether or not ginkgo affects coagulation, routine indices do not reflect any disturbance [57,58]. Between this visit and the next, the patient developed hot flashes. Amid the possible remedies at the health food store, she selected red clover. A member of the Leguminosae family, red clover contains coumarins [59]. Unaware, this patient may have just added another anticoagulant to her regimen. Over the next few months, she is busy with work. She is feeling low in energy, she is not exercising, she is gaining weight, she thinks her complexion has developed a pallor. Again, evaluation by her primary care physician is negative. One night, on the Internet, she comes across a Chinese medicine site featuring a pretty bottle containing a formula referred to as Women’s Precious. Often the Chinese names are translated to musical, flowery names. Alternative names for the formula include Eight Treasure Decoction, although there are others. This is a formula commonly used to treat certain menstrual or menopausal disturbances, often when associated with fatigue. The site included a list of complaints for which the formula might be indicated, which led this patient to believe the formula might be helpful. When she reviewed the ingredient list, she noted that many of those listed were also in the tea she had gotten from me when she first presented to my office. She was not aware that the doses and combinations could change their effects. Nor did she understand that at least two of the components, angelica and ligusticum, contain coumarins and ligustilide, respectively, with potential anticoagulant effects [60,61]. It is notable that when combination formulas contain herbs which may decrease coagulation, they also contain prothrombotic herbs. This is the case with Women’s Precious [62]. Another aspect of anticoagulant herbs is that many of them also contain prothrombotic compounds. The leech is the best known example. As I have discussed, the coumarins are a complex lot, and they are only
Dilemmas in herbal medicine: The clinician’s viewpoint one compound present in the plants from which they have been isolated. Coumarins provide us with aflatoxin, yet they also show anti-neoplastic activity. Might it be that plants containing anticoagulant coumarins also contain compounds supporting coagulation? Depending on the dose or other conditions, one effect or another may predominate, in a way similar to the biphasic response to dopamine depending on whether the dose is low or high [63]. This is discussed further in the review of research priorities, which will be presented tomorrow. We have limited access to Chinese medical literature which may discuss safety of herbal medicine. It is clear, however, that potent Chinese medicines were not meant to be used in a medically unmonitored setting. They were meant to be used in combination with numerous other products such as this patient, and many others, have done [64]. The next stage of this patient’s story happens shortly before this meeting. She reads in the newspaper about a report that women in her age range who experience from migraines with aura are at increased risk for stroke [65]. She ponders whether she should add aspirin to her regimen. Fortunately it is time for her yearly visit with me, and holds the question for her appointment. In the case of older patients, there is additional risk for complications. All the considerations that have been reviewed in the previous case apply. In addition, older patients are often on multiple medications. They may have hepatic or renal insufficiency, with decreased excretion of active principles, and possible buildup of active metabolites. These possibilities are largely cause for speculation, since pharmacologic and pharmacokinetic characteristics of herbs and supplements are not well defined. Furthermore, the elderly have increased vascular fragility, predisposing them to bleeding, and impairment of balance which contributes to falls and injury [66]. And finally, from what I have seen, there is usually somebody, somewhere in their life eager to help, who brings them a product recommendation. . . or two. In most cases, when I see complex or elderly patients who request a treatment regimen, my intervention centers or reducing what they are taking, rather than giving something. Most commonly, when they present at the time of the first visit with their shopping bag full of bottles, I prune their program. In addition to looking behind me to see what problems are lurking, I also look forward to see what lessons herbs can teach us about how to treat disease. When I first began studying herbs as I described at the start of the talk, I was a bit skeptical as I read about studies done in China
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which elucidated numerous diverse effects. It seemed that for plant after plant, isolates demonstrated effects that were immune-enhancing, anti-inflammatory, and anti-cancer. Today we are seeing evidence that inflammation has a close tie to cardiovascular disease and cancer, among other conditions [67,68]. It is also now understood that inflammation and hypercoagulability are also closely related [69], especially but not exclusively in the hypercoagulable state of malignancy. It has been suggested that in seeking better treatments for the hypercoagulable state of cancer, positive effects on tumor growth and dissemination may also be obtained [70]. Interestingly, there have been encouraging outcomes resulting from examination of treatment of malignancy with coumarins, including warfarin [71]. As a clinician I am obligated to consider patient safety, yet I have also taken on the task of treating patients who consider what I offer to be a last resort. In this capacity, I propose the question: how can we use natural products, or natural product constituents, with their seemingly, but not truly diverse effects, to improve treatment of many of today’s difficult diseases, including thromboembolic conditions?
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