Lectures on Natural Products

1. Lectures on Natural Products PHAR331 - Fundamentals of Drug Action Recitation for Dr. A. D. Kinghorn Fall 2000

2. Lectures on Natural Products • Alkaloid Extraction • Lead Drugs from Nature: Epibatidine • Overview of the Use of Botanical Drugs in the U.S.

3. H2O (neutral or basic) CHCl3 lipophilic mixture NR3 Alkaloid Extraction

4. H2O/H+ NR3H+ CHCl3 lipophilic mixture Alkaloid Extraction

5. Natural Products as Leads for Drug Development:Epibatidine • “Poison dart frogs” used as arrow poison by Amazonian natives • Skin of many Dendrobatidae frogs found to be rich in biologically active alkaloids • Epibatidine represents a new class of analgesic agents

7. Structure and Biological Activity of the Straub-tail Alkaloid • 1976: 750 frog skins yield less than 1 mg • “Epibatidine” 200 times more effective than morphine as analgesic • Mode of action through the nicotinic receptor-channel (nAChr)

8. From Jungle to Clinic • Researchers at Abbott intrigued by the structural similarity of epibatidine and a group of nicotine analogs already under investigation for Alzheimer’s disease • Screening for analgesic potential of over 500 nicotine analogs leads to ABT-594 • ABT-594: • antinociceptive properties equal to those of morphine • lack of opioid-like withdrawal and physical dependence

9. Overview of the Use of Botanical Drugs in the United States Today • The market for botanicals has grown from a grass roots industry 25 years ago to a $3.6 billion retail value in 1997 • According to the Dietary Supplement Health & Education Act of 1994, botanical drugs (phytopharmaceuticals) are regulated as dietary supplements rather than drugs. Therefore, no health claims are allowed on the product labels

10. Botanical Drugs... • The top ten herbal products sold in retail outlets in the U.S. in 1997 were: Ginkgo, Ginseng, Garlic, Echinacea/Goldenseal, St. John’s Wort, Saw Palmetto, Grapeseed, Cranberry, Valerian, Bilberry, Milk Thistle and Kava • The ten products accounted for about 50% of all legal herbal product sales in 1996. Some 300 other botanicals available over-the-counter in the U.S. accounted for the other half

11. Botanical Drugs... • Phytopharmaceuticals are used as single herbs, herb combinations, and in combination with non-herbal ingredients • Botanicals are sold in the form of capsules, tablets, herbal teas, extracts, tinctures and bulk herbs

12. Some Common Myths About Phytopharmaceuticals Sold in Pharmacies and Health Food Stores • The efficacy of all of these products has been determined beyond doubt in European countries such as Germany. • Some clinical studies have been performed, but most of these are considered inconclusive. • The active principle(s) of herbal drugs are all well-defined. • This is the exception rather than the rule. In some cases (e.g., ginkgo, the observed biological activity is known to result from a combination of plant secondary metabolites).

13. Myths... • The botanical drugs offered for sale are of the stated quality. • The identity of most herbal drugs is a very gray area, since monographs for their quality control (standardization) are only just now being compiled. Problems with poor quality or contamination/adulteration are frequently encountered in some brands of botanical drugs. • The phytopharmaceuticals for sale in pharmacies are safe. • Since these products are recommended for mild disease conditions, this is probably true provided one keeps to the stated dose.