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Articles and Publications
Perspectives: Mainstreaming Alternative Medicines: Botanicals and Other Complex Natural Products as Prescription Drugs
Complementary and alternative medicine Those patients who experience suboptimal clinical responses to current treatment regimens often seek out alternative treatments. Use of "complementary and alternative medicine" (CAM) is quite prevalent in people with epilepsy.[Schachter-2008] CAM includes herbal and other natural medicines, many of which have been used historically to treat neurological disorders (see Table 1), but have not been formally tested or evaluated by the FDA to date. Although mainstream drugs often contain a single compound ("active") derived from natural products, plant extracts comprised of complex chemical mixtures have not been a part of US medicine— at least not until recently. In the US, botanicals were historically used as drugs up until the passage of the Kefauver-Harris Act in 1962. The law amended the federal Food, Drug and Cosmetic Act to impose rigorous requirements on the US Food and Drug Administration (FDA) to affirm the safety and efficacy of all drugs marketed after 1938. To study the clinical effects of a botanical extract or food as a treatment or prevention of seizures, an Investigational New Drug (IND) application must be filed with the FDA. This requires the submission of not only a clinical section (study protocol, investigator credentials and consent form), but also detailed information about the chemistry, manufacturing and controls (CMC) of the study product. Botanicals and herbals For botanicals, product sponsors were stymied as to how to conform to FDA’s CMC requirements, since for some products there was no specific "active", and for others there were too many "active" constituents to characterize. As a result very few "pre-1962" botanical ingredients remain on the US market as drugs. As a product class, botanicals did not return to the US market in any numbers until the passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994. This could be attributed in part to DSHEA’s explicit mention of "botanicals and herbals" as "dietary ingredients" for use in dietary supplements. By this time there was also the misperception that complex mixtures could no longer be marketed as drugs in the US. The above may explain why in the US the majority of natural ingredients are sold today as foods, including "dietary supplements." In foreign countries the same products and ingredients may be classified as "herbal" or "traditional" medicines or drugs. Contrary to other regulatory systems, products are regulated in the US by their intended use. A product intended to be used to diagnose, treat, prevent, mitigate or cure a disease condition, such as epilepsy or seizures, and which exerts its effect by affecting the structure or function of the body, is considered to be a "drug," regardless of the source or nature of its ingredient(s), or how it is currently being marketed in the US. Botanicals not intended as treatment No prohibition exists for physicians to recommend botanicals to their own patients or for consumers to self-medicate with these products. However, such products are not intended to be used to treat or prevent disease, disease symptoms or the side effects of mainstream interventions, and rigorous evidence of their effectiveness and safety is often lacking. Further, manufacturing requirements for foods and "dietary supplements" are far less rigorous than for drugs, and unlike drugs, there is no criterion that foods or supplements must demonstrate "efficacy". In June 2004, FDA published a "Guidance for Industry for Botanical Drug Products" in which it defines a "botanical" as any product that "contains ingredients of vegetable matter or its constituents as a finished product." The guidance provides recommendations for developing botanicals and other complex mixtures for the US market as drugs and describes the IND process for botanical drugs, focusing on the CMC and toxicological sections of the application. According to this guidance, for a botanical drug, documentation of the product’s identity (genus, species, cultivar), sourcing (growing conditions, harvesting, processing), characterization (HPLC "fingerprint"), standardization (biomarkers, lot-to-lot consistency), potency and stability and manufacturing process validation are needed to ensure reproducibility of the clinical results. Safety data from both nonclinical (animal) testing, and prior human use (if available), and efficacy data must be collected or established in "adequate and well-controlled" trials. Data submitted to the IND eventually serve as the basis of a New Drug Application (NDA) to permit marketing of the drug. To approve an NDA, FDA must affirm that the data support the drug’s benefits and that these outweigh any risks to the intended "target" population. FDA approval To date, the FDA has received nearly 400 "pre-IND" meeting requests and IND applications for botanical drugs. FDA recently approved two NDA applications for naturally complex drugs. An omega-3 drug derived from salmon oil, [originally called Omacor®; Ross Laboratories; licensed to Reliant Pharmaceuticals, NJ; and now marketed under Lovaza®] was approved in November 2004, as "an adjunct to diet to reduce very high (≥500 mg/dL) triglyceride (TG) levels in adult patients." In October 2006, FDA approved the first complex botanical drug, a green tea extract [Veregen®, Medigene; Munich] as a topical treatment for genital warts. As approved drugs, both of these complex natural products were able to meet the legal criteria for safety and efficacy, and they are manufactured to the same quality standards as other prescription drugs in the United States. While no complex botanical drugs have yet been approved by FDA for use in epilepsy, their polymolecular nature may theoretically be able to impact a multitude of cellular targets, and it is likely that further developments will be made in the testing and development of complex botanical drugs for the treatment of epilepsy. =//= TABLE 1: Complex Botanical Ingredients Traditionally Used for Epilepsy and Other Neurological Conditions (Caution: Rigorous Evidence for their Safety and Efficacy is Generally Lacking)
Source: Chart created by HeteroGeneity, LLC for epilepsy.com REFERENCES: Dietary Supplement Health and Education Act of 1994 [Public Law 103-417] [amended the FD & C Act, Section 411(c)(1)(B) (21 U.S.C. 350(c)(1)(B))] Eadie MJ. Could valerian have been the first anticonvulsant? Epilepsia. 2004 Nov;45(11):1338-43. Elferink, J. Epilepsy and Its Treatment in the Ancient Cultures of America. Epilepsia 1999;40(7):1041-1046. Epilepsy Ontario – Epilepsy in the South Asian Community. [http://www.epilepsyontario.org ] Federal Food, Drug and Cosmetic Act §201(p)(1) Food and Drug Administration, Center for Drug Evaluation and Research: Guidance for Industry - Botanical Drug Products (Chemistry) June 2004. (www.fda.gov/cder/guidance/4592fnl.pdf) Hijikata Y: Bu-yang-huan-wu-tang: Decrease in the number and severity of seizures. J of Alt-Compl Med. 2006 12(7):673-7. Hijikata Y, Yasuhara A, Yoshida Y, Sento S. Traditional Chinese medicine treatment of epilepsy. J Altern Complement Med. 2006 Sep;12(7):673-7. Hsieh CL, Lin JJ, Chiang SY, et al.: Gastrodia elata modulated activator protein 1 via c-Jun N-terminal kinase signaling pathway in kainic acid-induced epilepsy in rats. J Ethnopharmacol. 2007 Jan 19;109(2):241-7. Epub 2006 Jul 25. Khan R, Krishnakumar A, Paulose CS. Decreased glutamate receptor binding and NMDA R1 gene expression in hippocampus of pilocarpine-induced epileptic rats: neuroprotective role of Bacopa monnieri extract. Epilepsy Behav. 2008 Jan;12(1):54-60. Liu JM, Jiang T. [Pondering on the diagnosis and treatment criteria for syndromes of epilepsy in traditional Chinese medicine] Zhong Xi Yi Jie He Xue Bao. 2006 Nov;4(6):572-4. [Article in Chinese] Luo Y: Ginkgo biloba extract [EGb761]: neuroprotective potency under conditions such as ischemia, seizures and peripheral nerve damage. J Alzheimer Dis 2001 3(4):401-7. Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Rev Neurol Dis. 2007 Spring;4(2):103-6. Ojemann LM, Nelson WL, Shin DS, et al.: Tian ma, an ancient Chinese herb, offers new options for the treatment of epilepsy and other conditions. Epilepsy Behav. 2006 Mar;8(2):376-83. Epub 2006 Feb 7. Peredery O; Persinger MA: Scutellaria lateri flora (Skullcap), Gelsemium sempervirens (Gelsemium), Datura stramonium (Jimson Weed): preclinical (rats) decrease the number and severity of spontaneous seizures. Phytother Res 2004 18(9):700-5.] Samuels N, Finkelstein Y, Singer SR, Oberbaum M. Herbal medicine and epilepsy: Proconvulsive effects and interactions with antiepileptic drugs. Epilepsia. 2008 Mar;49(3):373-80. Epub 2007 Oct 15. Schachter S. Complementary and alternative medical therapies. Curr Opin Neurol. 2008 Apr;21(2):184-189. Schlanger S, et al: Omega-3 oils: dietary supplementation may suppress some cases of epileptic seizures. Epilepsia. 2002 43(1):103-4. Shaklee [http://content.nhiondemand.com/shp/tcHC.asp?objID=100963] Spinella M: Herbal medicines and epilepsy: The potential for benefit and adverse effects. Epilepsy Behav 2001; 2(6):524-532. Sucher NJ. Insights from molecular investigations of traditional Chinese herbal stroke medicines: implications for neuroprotective epilepsy therapy. Epilepsy Behav. 2006 Mar;8(2):350-62. Epub 2006 Feb 7. Sugaya E, Jin W, Sugaya A, Sunaga K, Tsuda T. Inhibitory effects of peony root extract on the large conductance calcium-activated potassium current essential in production of bursting activity. J Herb Pharmacother. 2006;6(2):65-77. Sugaya A, Suzuki T, Sugaya E, et al. Inhibitory effect of peony root extract on pentylenetetrazol-induced EEG power spectrum changes and extracellular calcium concentration changes in rat cerebral cortex. J Ethnopharmacol. 1991 May-Jun;33(1-2):159-67. Wilner, A: Botanicals Take Center Stage at AES. [02/02/2006] http://professionals.epilepsy.com/page/ar_1138908904.html Zhao J: Nutraceuticals, nutritional therapy, phytonutrients, and phytotherapy for improvement of human health: a perspective on plant biotechnology application. Recent Patents on Biotechnology 2001 (1):75-97. About the author: Submitted on April 20, 2008 Submitted: 04/23/08 |
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FDA-approved treatment options for people with epilepsy include medications
and vagus nerve stimulation. Special diets, especially for children, and brain
surgery may be very beneficial as well for selected patients. However,
approximately 1 in 3 persons with epilepsy taking medications do not achieve
adequate control of seizures and another 1 in 3 experience side effects that
interfere with daily activities. Consequently, there continues to be a need for
new and well tolerated treatments. 
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