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IKHLAS A. KHAN

An overview of standardization of botanicals: USA perspective. IKHLAS A. KHAN National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi. Herbal Medicines - Main issues. Safety Quality (Authenticity ?)

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IKHLAS A. KHAN

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  1. An overview of standardization of botanicals: USA perspective IKHLAS A. KHAN National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi

  2. Herbal Medicines - Main issues • Safety • Quality (Authenticity ?) • Efficacy Biological Environmental Chemical Standardization Selection of marker compounds Adulteration/misidentification

  3. Safety

  4. Biological contaminants

  5. Heavy metals Pesticides (quintozene) Environmental Contaminants In ginseng products

  6. Concentration Range (ng/g) of DDT and its Metabolites in Select Botanical Supplements

  7. Heavy Metals - Comparison USA Europe China

  8. Herbal Sexual Enhancers Not So Herbal!

  9. Chemical Safety Aristolochic Acid • Aristolochic acid I and II present in Aristolochia appear to be responsible for Chinese herbs nephropathy (CHN). • Renal interstitium, mutagenic, and carcinogenic activity • Snakebites, rheumatism, as a diuretic and analgesic. Aristolochia macrophylla

  10. FDA Listing of plants known or suspected of containing aristolochic acids (updated April 9, 2001)1 Aristolochia Asarum Cocculus C. carolinus C. diversifolius C. hirsutus C.indicus C. laurifolius C. leaebe C. madagascariensis C. orbiculatus C. palmatus C. pendulus C. thunbergii A. canadense2 A. himalai(y)cum3 A. splendens3 A. forbesii3 A. heterotropoides3 A. sieboldii3 A. acuminata A. argentina A. baetica A. bracteata A. chilensis A. cinnabarina A. clematitis A. contorta A. cymbifera A. debilis3 A. elegans A. esperanzae A. fangchi3 A. fimbriata A. indica A. kaempferi A. kwangsiensis A. macrophylla A. manschuriensis3 A. maurorum A. maxima A. mollissima A. pistolochia A. rigida A. rotunda A. serpentaria A. watsoni(i) A. westlandi(i) A. zollingeriana Akebia Other species listed A. quinata3 A. trifoliata Bragantia wallichii Diploclisia affinis Diploclisia chinensis Menispernum dauricum Saussurea lappa Sinomenium acutum3 Stephania tetrandra3 Vladimiria souliei3 Clematis C. armandii C. chinensis C. hexapetala C. montana C. uncinata 1. http://www.cfsan.fda.gov/~dms/ds-bot2.html 2. Doskotch, R.W. and Vanevenhoven, P.R. Lloydia1967, 30(2), 141. 3. Hashimoto, K.; Higuchi, M.; Makino, B.; Sakakibara,I.; Kubo, M.; Komatsu, Y.; Maruno, M.; Okada, M. J. of Ethnopharmacology 1999, 64, 185.

  11. MW Aristolochic Acids AAI or A R1, R2, R3, R5 = H; R4 = OCH3; R6 = OH 341 AAIa R1, R2, R3, R5 = H; R4 = OH; R6 = OH 327 AAII or B R1, R2, R3, R4, R5 = H; R6 = OH 311 AAIII R1, R3, R4, R5 = H; R2 = OCH3; R6 = OH 341 AAIIIa or C R1, R3, R4, R5 = H; R2 = OH; R6 = OH 327 AAIV R1, R3, R5 = H; R2 = OCH3; R4 = OCH3; R6 = OH 371 AAIVa or D R1, R3, R5 = H; R2 = OH; R4 = OH; R6 = OH 357 AAVa R1, R4, R5 = H; R2 = OH; R3 = OCH3; R6 = OH 357 AAVIa R1, R2, R3 = H; R4 = OCH3; R5 = OH; R6 = OH 357 AAVIIa R1, R2, R5 = H; R3 = OH; R4 = OCH3; R6 = OH 357 AA E R1, R2, R5 = H; R3 = OCH3; R4 = OH; R6 = OH 357 AAI methyl ester R1, R2, R3, R5 = H; R4 = OCH3; R6 = OCH3 355 AAIa methyl ester R1, R2, R3, R5 = H; R4 = OH; R6 = OCH3 384 AAII methyl ester R1, R2, R3, R4, R5 = H; R6 = OCH3 325 AAIII methyl ester R1, R3, R4, R5 = H; R2 = OCH3; R6 = OCH3 355 AAIIIa-6-O-b-O-glucoside R1, R3, R4, R5 = H; R2 = Ogluc; R6 = OH 488 AAVII methyl ester R1, R2, R5 = H; R3 = OCH3; R4 = OCH3; R6= OCH3 386

  12. Chromatogram Comparison of Purchased Aristolochic Acid Standards 70% 1 20% 97% 4a* 2% 72% 2 25% 65% 4b* 28% 3 73% 24% *Same company, different batch number

  13. Chromatograms of Asarum canadense Populations Collected 59 IN: Perry Co. 77 SC: Berkeley Co. 88 NY: Cattaraugas Co. 62 IN: Crawford Co. 68 NC: Swain Co. 89 OH: Morgan Co.

  14. Quality • Standardization • Selection of maker compound/fingerprinting • Adulteration /misidentification

  15. Standardization Basic needs • ACTIVE COMPOUNDS • MARKER/REFERENCE COMPOUNDS

  16. Standardization ANALYTICS DIRECT APPLICATIONS FUTURE DEVELOPMENTS • BIO-ANALYSIS • CULTIVATION • GENETICS • ENVIRONMENTAL

  17. Standardization DIRECT APPLICATIONS • TO DEVELOP ANALYTICAL METHODS • PRECISION, ACCURACY, SPECIFICITY, LINEARITY, • RUGGEDNESS, ROBUSTNESS • TO DEVELOP FINGERPRINTS • SEMIPREP AND PREPARATIVE ISOLATION

  18. ANALYSIS ANALYTES

  19. Standardization We would like to have a method Applicable to all sort of preparations includes all the desirable markers can be used for quality control can be used for efficacy measurement BUT Don’t know the nature of a preparation Don’t know the marker compounds Don’t know the active compound Don’t know about the variability of the extract.

  20. 200 nm

  21. Ginseng • Panax ginseng and P. quinquefolium (Araliaceae) • Saponins (ginsenosides/ panaxosides) • ADAPTOGEN: tonic, immunostimulant, aphrodisiac. Also in high cholesterol, heart attacks, diabetes, cancer, liver protection, radiation therapy, and loss of appetitec

  22. Nomenclature of Ginseng SCIENTIFICCOMMON (Ginseng) Panax quinquefolium American, Occidental, Canadian Panax trifolius Dwarf Ginseng, Groundnut Panax Ginseng Oriental, Chinese, Korean, Red, White Tartary, Kirin Panax notoginseng Sanchi, Tienchi, Sanchu Panax japonicus Japanese, Chiku Panax pseudoginseng Himalayan Panax elegantior Pearl Eleutherococcus Siberian, Russian, Eleuthro sentocosus Touch-me-not Devil’s Bush

  23. Misnamed Ginsengs BRAZILIAN GINSENG SUMA (Pfaffia paniculata) INDIAN GINSENG ASHWAGANDA (Withiana somnifera) ALASKAN GINSENG DEVIL’S CLUB (Oplopanax horridum) AMERICAN RED CANIAGRE (Rumex hymenosepalus) DESERTGINSENG

  24. St. John’s Wort • Hypericum perforatum (Hypericaceae) • Naphthodianthrones (hypericin, pseudohypericin, hyperforin), flavonoids • In mild depression

  25. Analysis of rutin (1), hyperoside (2), isoquercitrin (3), quercitrin (4), quercetin (5), I3,II8 biapigenin (6), pseudohypericin (7), hypericin (8) and hyperforin (9) in different H. perforatum products

  26. Variations in the peak area of 1-9, if one H. perforatum sample (P-N-6) is extracted with different solvents Extraction

  27. Percentage (g/100 g) of flavonoids (1-6), naphthodianthrones (7,8) and hyperforin (9) in products Products Analysis

  28. Indian sample 2 1 3 4 1 1 Tribulus Market products

  29. Bulgarian sample different plant parts shoots of 2 species leave 1 1 T. terrestris (Utah) fruit 1 T. cistoides (Florida) stem 1

  30. Uncaria tomentosa

  31. Selection of Marker Compounds • Tanacetum parthenium L., Asteraceae • For migraine prophylaxis • Parthenolide is the major component (active constituent ?)

  32. In Magnolia leaf Parthenolide In Feverfew Abourashed & Khan, JAOAC, 2000.

  33. Parthenolide 4.5 Cost: Dollars/day 4 3.5 Parthenolide: mg/day 3 2.5 2 1.5 1 0.5 0 FF1 FF2 FF3 FF4 FF5 FF6 FF7 FF8

  34. New Indications Toxicological Evaluation Clinical Studies Quality Plant Material Well-Characterized: Botanically Chemically Pharmacologically Stability Drug Interactions Formulated Products New Crops

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