Yunnan baiyao for patients with hemorrhage, neoplasia December 11, 2017 By Brennen McKenzie, MA, MSc, VMD, cVMAPreclinical studies of some of the ingredients indicate a variety of biological effects in vitro and in animal models. Some of these effects might support the purported procoagulant activity. Herbal remedies are widely available to animal owners as over-the-counter products intended for both human and veterinary use. Some veterinarians prescribe these remedies, usually as part of a broader complementary and alternative medicine approach. One survey of pet owners at a university oncology center found approximately 18 percent of these owners reported using botanical treatments,1 but it’s unclear how commonly herbal remedies are used in veterinary patients generally. There are many issues owners and veterinarians should consider before using herbal remedies for pets. I will illustrate these with the example of yunnan baiyao (YB), a Chinese medicine remedy sometimes recommended for patients with hemorrhage or neoplasia (though some sources list dozens of unrelated medical applications).2 Biologic plausibility Biologic plausibility is an important epidemiologic criterion for causal relationships in medicine, including the relationship of efficacy, in which a therapeutic intervention produces a meaningful beneficial change in the patient’s condition.3 Plausibility is often defined as a proposed relationship between treatment and effect that is consistent with established scientific knowledge. Evaluating plausibility involves assessing the consistency between the rationale and principles of use with established principles of physiology, pharmacology, and other relevant scientific fields. Because scientific knowledge is always incomplete and imperfect, not every true causal relationship in medicine will be consistent with current knowledge. However, those putative relationships that are inconsistent with well-established scientific principles are far less likely to be true than those that are not. In the case of YB, as for many herbal remedies, rationales and proposed mechanisms vary from highly implausible to moderately plausible. Many proponents of this remedy use the system of traditional Chinese medicine (TCM) to guide selection and use of YB and other Chinese herbal products. This is a prescientific set of philosophical concepts and folk beliefs involving balancing of vital humors and spiritual forces to prevent and treat disease. Herbal remedies are chosen according to supposed relationships between the taste or physical appearance of plants or other ingredients and these humors or energies.4 As an example, in this model, one of the plant constituents of YB, Panax notoginseng, is judged sweet and slightly bitter in taste and so should “transform stasis, resolve stagnation, tonify qi, invigorate blood, and clear heat.”2 Such unscientific folk medicine practices do not provide a plausible or rational basis for herbal prescribing. There also are more scientific proposed rationales for the claimed effects of YB. Preclinical studies of some of the ingredients indicate a variety of biological effects in vitro and in animal models. Some of these effects might support the purported procoagulant activity, 5-8 but other studies do not show such effects.9-14 Overall, the in vitro and lab animal studies are varied and conflicting, and the body of evidence does not provide a clear plausible rationale for the many often incompatible clinical effects claimed. Uncertain ingredients As with many herbal remedies, the precise ingredients in YB are proprietary. Several lists of possible constituents have appeared online, but these are inconsistent, and there is no standardization or accurate disclosure of how much of each ingredient is present. As the chemical composition of plants varies, herbal remedies often have different compositions with every batch, which can affect both safety and efficacy. It is well documented that herbal products can be contaminated with undisclosed toxins and even pharmaceuticals.15-20 For example, batches of YB have been found to contain lead, and some sources report that it contains progesterone.21-22 Serious injury and death in humans have been linked to such adulteration of herbal remedies.23 Voluntary industry self-regulation has been proposed to mitigate these concerns.24 However, such self-regulation is not an approach most of us would consider acceptable for pharmaceutical medicines, and the rationale for lower standards for herbal remedies is unclear. Clinical trial evidence Most herbal remedies have not been subjected to reliable clinical trial testing. This is largely because there is no regulatory requirement to prove safety and efficacy before marketing or using such products. It is also difficult to test herbal remedies when the ingredients are often unknown or inconsistent, and when indications and rationales for use are highly variable and often involve unscientific systems like TCM. It is also sometimes claimed that a lack of financial resources of incentives prevents proper testing of these products, but it is worth noting that the herb and supplement business is a multi-billion-dollar industry.25 In the case of YB, a recent systematic review of studies done in humans found some evidence of possible beneficial effects but also found that 1) most of the published research was of low quality and at high risk of bias, 2) for some conditions the apparent effect disappears when lower quality studies are excluded, and 3) there is evidence of publication bias, in which negative studies remain unpublished, creating an inaccurate impression of the true state of the evidence. Overall, the authors stated that, “Great heterogeneities and possible publication bias were found among the trials which preclude certain conclusions.”26 Table 1 summarizes the literature in veterinary species over the past 40 years. Of these 11 studies, six found no effect at all, and two others showed mixed results. Of the three positive studies, two did not report any of the key methods for limiting bias and other errors. Several of the studies did not find the procoagulant effects suggested by the preclinical research, which undermines the biologic plausibility for the product. While no serious adverse events have been reported for YB, no study has specifically evaluated safety, and the inconsistency in composition and usage for YB makes it difficult to ascertain what risks it may present. Such limited and inconsistent evidence is typical for the veterinary herbal medicine research, when there are any studies at all. Most herbal products do not have even this level of evidence for us to evaluate. The best that can be said is that there are plausible potential mechanisms for some when not used according to metaphorical folk medicine systems. However, the true benefits and risks of herbal products are almost always unknown even for those, which, like YB, have been used and studies for decades. Bottom line All therapies with real benefits have risks. Pharmaceutical medicines, which are studied and regulated to a much greater extent than herbal products, can have unpredictable and unacceptable risks or less efficacy than expected once they go from research to clinical use. There is no good reason to believe the plant chemicals and other active compounds in herbal remedies will be exempt from such undesirable and unpredictable effects, especially when they are often used with far less evidence and less plausible rationales than conventional medicines. When considering use of such remedies, owners and veterinarians should evaluate biologic plausibility, avoid the use of metaphorical folk systems to guide herbal prescribing, consider the risks posed by inconsistent composition and lack of regulatory oversight, and critically evaluate the clinical trial literature. Often, the degree of uncertainty concerning safety and efficacy will be high, and owners should be fully informed of this. References Lana SE, Kogan LR, Crump KA, et al. The Use of Complementary and Alternative Therapies in Dogs and Cats With Cancer. J Am Anim Hosp Assoc 2006;42(5):361-365. Gruenstern J. Yunnan Baiyao-Miracle herb for your clinic. Integr Vet Care J 2014;4(1):26-28. Weed DL, Hursting SD. Biologic plausibility in causal inference: Current Method and practice. Amer J Epid 1998;147(5):415–425. Xie H. Preast V. (2013). Traditional Chinese Veterinary medicine: Fundamental Principles. 2nd Reddick, FL: Chi Institute Press. Ogle CW, Dai S, Ma JC. The haemostatic effects of the Chinese herbal drug Yunnan bai yao: A pilot study. Am J Chin Med 1976;4:147–152. Ogle CW, Soter D, Cho CH. The haemostatic effects of orally administered yunnan bai yao in rats and rabbits. Compar Med East and West 1977;5(2):155-160. Graham L, Farnsworth K, Cary J. The effect of yunnan baiyao on the template bleeding times and activated clotting times in healthy ponies under halothane anesthesia. J Vet Emerg Crit Care 2002;12(4):279. (abstract only) Fan C, Song J. White CM. A comparison of the hemostatic effects of notoginseng and yun nan baiyao to placebo control. J Herb Pharmacother 2005;5:1–5. Epp TS, McDonough P, Padilla DJ, et al. The effect of herbal supplementation on the severity of exercise-induced pulmonary haemorrhage. Equine and Comparative Exercise Physiology 2005;2:17-25. Lee A, Boysen SR, Sanderson J, et al. Effects of Yunnan Baiyao on blood coagulation parameters in beagles measured using kaolin activated thromboelastography and more traditional methods. International Journal of Veterinary Science and Medicine 2017;5(1):53–56. Frederick J, Boysen S, Wagg C, Chalhoub S. The effects of oral administration of Yunnan Baiyao on blood coagulation in beagle dogs as measured by kaolin-activated thromboelastography and buccal mucosal bleeding times. Can J Vet Res2017;81(1):41-45. MacRae R, Carr A. The Effect of Yunnan Baiyao on the Kinetics of Hemostasis in Healthy Dogs. ACVIM Forum, National Harbor, MD, 2017. Adelman L, Olin S, Egger CM, Stokes JE. Effect of Oral Yunnan Baiyao on Periprocedural Hemorrhage and Coagulation in Dogs Undergoing Nasal Biopsy. ACVIM Forum, National Harbor, MD, 2017. Ness SL, Frye AH, Divers TJ, et al. Randomized placebo-controlled study of the effects of Yunnan Baiyao on hemostasis in horses. Am J Vet Res 2017;78(8):969-976. Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol1997;37(4):344-50. Saper RB, Phillips RS, Sehgal A, Khouri N, Davis RB, Paquin J, Thuppil V, Kales SN. Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet. JAMA 2008;300(8):915-23. Debelle FD, Vanherweghem JL, Nortier JL (2008) Aristolochic acid nephropathy: a worldwide problem. Kidney Int 74:158–169. Calahan J, Howard D, Almalki AJ, et al. Chemical Adulterants in Herbal Medicinal Products: A Review. Planta Med 2016 Apr;82(6):505-1. Harris ESJ, Cao S, Littlefield BA, Craycroft JA, et al. Heavy metal and pesticide content in commonly prescribed individual raw Chinese herbal medicines. Sci Total Environ 2011;409:4297–4305. Coghlan ML. Deep sequencing of plant and animal DNA within traditional Chinese medicines reveals legality issues and health safety concerns. PLOS Genetics. 2012;8(4):e1002675. Shmalberg J, Hill RC, Scott KC. Nutrient and metal analyses of Chinese herbal products marketed for veterinary use. J Anim Physiol Anim Nutr (Berl). 2013;97(2):305-14. How can Yunnan Baiyao capsules help with your sick dog? (March, 2016) Accessed 8-21-2017 from bit.ly/2ikEdWp. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. Journal of Internal Medicine 2002;252: 107–113. Basko I. Behind the green door: Tangled herbaceutical testing. J Am Holistic Vet Med Assoc Apr-Jun 2003;22(1):31-35. Nahin RL, Barnes PM, Stussman BJ. Expenditures on complementary health approaches: United States, 2012. National Health Statistics Reports. Hyattsville, MD: National Center for Health Statistics. 2016. Bo Yang, Zhe-Qi Xu, Hao Zhang. et al. The efficacy of yunnan baiyao on haemostasis and antiulcer: a systematic review and meta-analysis of randomized controlled trials. Int J Clin Exp Med 2014;7(3):461-482. Murphy LA, Panek CM, Bianco D, Nakamura RK. Use of yunnan baiyao and epsilon aminocaproic acid in dogs with right atrial masses and pericardial effusion. J Vet Emerg Crit Care (San Antonio). 2016 Sep 26. doi: 10.1111/vec.12529. Dr. McKenzie discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.