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Botanicals Take Center Stage at AES
Washington, DC-A standing room only crowd attended the inaugural meeting of the Botanicals Special Interest Group (SIG) at the 59th Annual American Epilepsy Society Meeting. Steven Schachter, MD, Professor of Neurology, Harvard Medical School (HMS), and Associate Director of Research of the HMS Osher Institute, Boston, Massachusetts, coordinated the session*.
Dr. Schachter explained that herbal medicines have a rich tradition in many cultures around the world and are often taken by patients with epilepsy. Popular herbs include black cohosh, garlic, ginkgo biloba, ginseng, and St. John’s Wort. Of those patients who take herbs, 70% do so for their general health, 20% take them for other symptoms, and less than 10% take them to control seizures. In addition, he noted that most patients with epilepsy who use complementary and alternative medicines (CAM) do not discuss this with their doctors.
The Use of Herbal Medicine in China and Japan
According to Schachter, herbal medicines are widely used in China, constituting a fundamental component of Traditional Chinese Medicine (TCM). In Japan, herbal preparations, called ‘Kampo’, are manufactured using the same standards as prescription drugs and some are available only by physician prescription. Their mainstream status is further reinforced by the Japanese national health insurance’s policy of reimbursement.”
Some herbal extracts with a tradition of use in epilepsy and compounds isolated from them have mechanisms of action relevant to epilepsy while others have activity in animal models of epilepsy. In the Far East, clinical trials for epilepsy have been performed using 135 herbal drugs, and the results appear in 71 publications. These clinical trials, however, are generally published in Chinese and may be difficult to interpret by Western standards of study design and outcome measures.
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Challenges of Commercialization of Herbal Therapies
Challenges to developing herbal therapies for epilepsy include developing strategies for identifying and authenticating herbs, establishing intellectual property, material transfer, intra-species variability and seasonal variations, soil contaminants, uncertainty about active ingredients and dosing, lack of serum assays to guide dosing, designing and implementing clinical trials and insufficient federal standards for manufacturing and quality control.
Currently, herbal products are classified by the government as dietary supplements, not pharmaceuticals. Consequently, they do not undergo the same scientific and regulatory scrutiny as prescription medications. Herbal preparations may suffer from contamination or variable quantities of the active ingredient. At present, there is no herbal product with proven efficacy for epilepsy.
Dr. Schachter concluded, “Botanicals represent a good source of bioactive compounds. Studying botanicals may lead to the discovery of antiepileptic drugs with novel mechanisms of action and favorable safety profiles.”
Investigations of Traditional Chinese Herbal Stroke Medicines: Implications for Neuroprotective Epilepsy Therapy
Nikolaus J. Sucher, MD, Children’s Hospital and Harvard Medical School, Boston, MA, developed an intimate familiarity with TCM during 7 years of study in Hong Kong. Dr. Sucher explained that while basic science research has elucidated many of the mechanisms for neuronal injury and death due to stroke and status epilepticus, such as glutamate release, activation of receptors for excitatory amino acids, calcium influx into neurons, generation of free radicals, forms of programmed cell death (apoptosis) and inflammation, treatments targeting these mechanisms have been difficult to develop. The only approved treatment for stroke is thrombolysis, for which most patients are not eligible.
Dr. Sucher discussed his reasons for studying TCM as a source of potential neuroprotective therapies. “TCM offers a sophisticated system of medical theory and practice, which includes three main therapeutic modalities; acupuncture, moxibustion, and phytotherapy,” he said. Phytotherapy, according to Sucher, is the most widely practiced form of herbalism worldwide. Although phytotherapy has been practiced on millions of individuals for thousands of years, there is relatively little research regarding possible mechanisms of action of herbal treatments. Nonetheless, traditional Chinese herbal medicines appear to be effective clinically with few or no adverse effects.
In order to select which herbs to investigate, Dr. Sucher and his colleagues consulted ancient and modern textbooks of TCM, searched the Chinese and international scientific literature, and chose medicines from the Chinese Pharmacopoeia. The Chinese Pharmacopoeia contains information regarding approximately 535 drugs including 460 plant-derived herbal medicines. Most TCM prescriptions consist of combinations of several herbal medicines in order to accomplish 3 important goals: (1) maximize therapeutic efficacy through synergistic actions (mutual reinforcement), (2) ameliorate or prevent adverse effects (mutual restraint and detoxification), and (3) target more than one pathophysiological mechanism (mutual assistance). Because of the preference for combination therapy in TCM, it can be difficult to isolate the active ingredient(s) of a particular prescription. For example, a common prescription, Tianma Gouteng Yin, contains 11 different ingredients containing numerous potentially active compounds. It is also possible that single ingredients will not be active unless accompanied by the other drugs in the formula , making drug testing for efficacy extraordinarily complex.
Dr. Sucher and his colleagues embarked on a reductionist experimental approach. They selected clinically effective Chinese stroke drugs, prepared aqueous extracts, selected molecular targets such as the NMDA receptor and assayed the effect of the drug extract on these targets. Dr. Sucher highlighted his studies of Tianma Gouteng Yin, prescribed by TCM doctors to ‘calm excessive endogenous wind’. Initial results suggest that this decoction contains drugs acting as NMDAR antagonists, drugs acting as antagonists at PDZ binding domains , and drugs with caspase inhibitory activity . Thus, the decoction contains drugs with actions at several levels of the signaling pathway involved in neuronal injury and death. Some constituents of this decoction act as noncompetitive, low-affinity NMDAR antagonist. This mode of action may explain the absence of serious adverse effects related to NMDR blockade by this formulation. Tianma Gouteng decoction contains in addition a large number of other structurally diverse chemical compounds that might afford additional beneficial therapeutic effects as antioxidant and anti-inflammatory agents. In addition, Tianma Gouteng Yin blocked the effect of caspase 8, an enzyme involved with programmed cell death. While these mechanisms of action may be clinically important, Dr. Sucher conceded that it is not known whether these laboratory findings account for the clinical effects of Tianma Gouteng Yin.
Dr. Sucher summarized his results, “Chinese herbal medicines act in vitro on specific molecular targets involved in neuronal injury and death. Herbal drugs contain chemically diverse families of compounds that act with low-affinity at multiple targets. The data appear to support the multi-component, multi-target approach of traditional Chinese medicine.” In terms of future development, it is unclear whether single compounds isolated from herbal medicines should be developed , or whether combinations of herbal medicines would be better. He concluded, “Traditional Chinese herbal medicine is more than just a treasure trove of natural products. It is an example of ‘systems-oriented’ pharmacotherapy.”
Botanicals and Epilepsy: Clinical Aspects
Siegward-M. Elsas, MD, Assistant Professor of Neurology, Oregon Health and Science University, Portland, Oregon, focused his presentation on clinical evidence for the effectiveness of botanicals in the treatment of epilepsy. He asserted that there are a multitude of botanicals used traditionally for epilepsy. Of these, 5 examples were discussed including: Valerian (European traditional botanical),Passiflora incarnata (Native North and South American botanical), Kava kava (Pacific native botanical), Piper nigrum (Traditional Chinese Medicine), and Withania somnifera (Ayurvedic Medicine). He further stated that the scientific studies and clinical experience with these botanicals is very limited and formal clinical trials would be desirable to assess their efficacy.
Valerian, a European traditional herb, is used as a sedative/hypnotic. Active ingredients are valepotriates, which inhibit GABA metabolism and may also bind GABA receptors.
Passiflora incarnata, used by Native Americans as a sedative/anxiolytic, probably exerts its clinical effect via flavonoids. Initial studies suggest that Passiflora incarnata enhances GABAA receptor ligand binding and is a partial GABAA agonist. It inhibits PTZ-induced seizures in rodents. One clinical trial supports anxiolytic efficacy.
Kava-kava originates from the South Pacific region where it is consumed as a sedative ceremonial drink. Its active ingredients are kavalactones, which enhance GABAA receptor ligand binding, inhibit voltage gated Na+ and Ca++ channels and inhibit strychnine-induced seizures in rodents.
Piper nigrum (black pepper) is used in TCM and is an NMDA receptor antagonist. The compound ‘antiepilepsirine’ has been purified from this plant. Another TCM botanical is Cynanchum otophyllum, which inhibits kainic acid-induced seizures in rodents.
Ayurvedic Medicine offers Withania somnifera (Ashwagandha), which binds to the GABA receptor.
Challenges in Conducting Clinical Trials of Botanicals
According to Elsas, “there are several challenges which researchers face when designing and implementing clinical trials involving botanicals including: 1) which plant to choose and in which dose, 2) establishing the reproducibility of the plant extract, 3) avoiding adverse events, 4) measuring efficacy, and 5) ultimately obtaining regulatory approval. After identifying promising botanicals, Elsas suggested that their extracts be tested in the anticonvulsant screening program sponsored by the NINDS.
In order to insure reproducibility, plants must be correctly identified. In addition, there must be a reproducible source of the plants. Botanical potency may be influenced by the season of harvest, location, and weather conditions. Active ingredients must be identified and standardized. Establishing a chemical footprint by Thin Liquid Chromatography (TLC) or High Performance Liquid Chromatography (HPLC) are two techniques to standardize the chemical composition of botanicals.
Potential Health Risks
Botanicals are not without potential health risks. For example, there are recent reports of possible liver toxicity of Kava-kava. Both Ephedra and Ginko biloba may trigger seizures. Consequently, the available literature must be carefully studied for hints of toxicity prior to commencing clinical trials. The potential of cytochrome P450 induction or inhibition should be considered and drug-drug interactions anticipated. During clinical trials, anticonvulsant levels, liver and renal function must be carefully followed and patients screened for sedative and other adverse effects.
With respect to efficacy, the measurement tool should the 50% responder rate, not the average reduction in seizures, to allow for adequate statistical analysis. An active anticonvulsant may show at least 30% or more responders, while one should anticipate a placebo responder rate of about 10%. Regulatory approval will require preparation details of the herbal extract, absence of contaminants, and extract stability. For FDA approval, an IND must be submitted. The IND application process includes a primary review by the Neurology Division assisted by the Botanical Division. Formal pre-IND meetings are available. Because of the wide use of certain botanicals, the FDA may not require, on a case-by-case basis, animal safety data and phase I trials.
*At another AES program, Dr. Schachter received an Epilepsy Research Foundation Grant Award for his research, ‘In Vitro and In Vivo Testing of Herbal Extracts and Extract Derived Compounds for the Treatment of Epilepsy.’
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