top herbs latest research

A SPECIAL ALL-DIGITAL ISSUE VOLUME 5 ISSUE 2 $20.75 US January 2015

NATURALPRODUCTS

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Top Herbs, Latest

ResearchNew science fueling sales, opportunities in

the steady sector

2 • Botanicals Digital Issue • January 2015 | naturalproductsinsider.com

CONTENTS

NATURALPRODUCTS

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naturalproductsinsider.com

• •

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A SPECIAL ALL-DIGITAL ISSUEVol. 5, No. 2 January 2015

3 Viewpoint

5 Botanicals Research UpdateThere have been countless botanical-

focused studies published in the past

couple of years; here Steve Myers

focuses on the latest studies hitting the

pages of research journals throughout

the world.

12 For Entire Decade, U.S. Botanicals Market GrewIn 2013, Herbs and botanicals achieved

their biggest year of growth since the

late 1990s with retail sales exceeding

$6 billion. Josh Long breaks down the

numbers and what they mean for industry.

15 An Emerging Arena for Botanicals: Botanical DrugsApproximately one-quarter of the

prescription drugs sold in the United

States, Canada and Europe contain active

ingredients derived from plants, Robin

Koon of Best Formulations explains.

19 The Double Life of GalantamineThe Natural Product Association’s

Corey Hilmas, M.D., Ph.D., tells the tale

of galantamine, a unique botanical that

is both a dietary ingredient permitted for

use in dietary supplements as well as a

drug ingredient.

22 Takeaways for Your Business

• •

5


VIEWPOINT

Growing Season

From the beginning, plant life and human life have been intertwined. Drugs and synthetic chemicals have stolen a good deal of this limelight in the

past century, and it might have seemed like people forgot their roots, so to speak. However, plants were the original food and the original medicine, and recent data show consumers are increasingly returning to medicinal plants.

In both mainstream and natural channels, herbal products have flirted with double-digit growth during the last decade, despite worldwide economic challenges. What’s even more promising is the growing sales span a variety of herbs and uses. Many herbs carry traditional histories of use, including Chinese, Indian, Native American, Incan and Amazon Rainforest ancestry. Along with the backstories, new scientific evidence on the safety and efficacy of herbs are also driving sales.

The key is more consumers, especially the younger generations, believe in the healing power of herbs. Extending the bumper season of market growth into the next decade will require meeting the needs and desires of these eager consumers. This means ingredients backed by research, clean products and labels, transparent sourcing and manufacturing, safe and unadulterated products, sustainable supply chains, and innovative formulations that maximize multiple health benefits at a good purchasing value.

In this Botanicals Digital Issue, we explore the market sales and trends, and the latest scientific results on the most popular herbs that are contributing to the bountiful growth for herbal products.

Steve MyersSenior Editor(480) 990-1101 ext. [email protected]@stevomyers

When it comes to your label… Keep it clean. Keep it simple.

Growing consumer demand for unadulterated ingredients is globally changing what we put

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BOTANICALS RESEARCH

IN THIS ISSUE

Viewpoint p. 4

Botanicals Market p. 12

Table of Contents p. 2

Botanicals Research UpdateA look at the recent results from studies on plants

by Steve Myers

In the long history of humankind’s interest in plants as medicine, the current spate of research on the mechanisms and benefits

of botanicals is a blip. Fortunately, researchers are making up for lost time. There have been countless botanical-focused studies published in the past couple of years, but here we will focus on the latest studies hitting the pages of research journals throughout the world.

The relationship between research and sales is symbiotic, as the increase in positive study results boosts herbal sales, which then drive new efforts of scientific investigation. The end result is a stream of discoveries that promise to change health in real ways.

Some of the most popular herbal ingredients adding new research to their evidence files include cranberry, saw palmetto, flaxseed, ginkgo, ginseng, turmeric/curcumin and garlic.

Cranberry (Vaccinium macrocarpon) is well-researched and known for its ability to inhibit adhesion of bacteria, especially in the urinary tract. George Mason University, Virginia, researchers found A-type proanthocyanidins (PACs) from cranberries exhibited anti-biofilm (communities of bacteria that stick together on a surface) properties against Pseudomonas aeruginosa bacteria.1 The study, which involved mass spectrometry analysis of the proteomic effects of cranberry PACs, built upon earlier research that showed PACs inhibited formation of biofilm involving E. coli. Recently, researchers at Rutgers University’s Marucci Center for Blueberry and Cranberry Research and Extension reported organic cranberry powder (as CRAN naturelle™, from Fruit D’Or) hindered uropathogenic bacteria in a not-yet published study. Of the 20 healthy female subjects given cranberry powder, 80 percent showed significant anti-adhesion activity, with peak response time at 12 hours after supplementation; adding a buffered vitamin C and alpha lipoic acid combination supplement (as TransportC-Plus™, from Helios Corp.) did not improve anti-adhesion effects.

Beyond urinary tract protection, cranberry has shown promise in cardiovascular health. A recent trial published in the December issue of Nutrition Research looked at the

INSIDER's Take

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¾ Both natural and pharma health researchers have poured efforts into discovering its benefits and mechanisms.

¾ Cranberry may be helpful to more than just the urinary tract, with recent results showing cardio/anti-inflammatory potential.

¾ Heart healthy garlic may also be beneficial in spinal cord injury, an area of health care in desperate need of remedies.

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BOTANICALS RESEARCH

anthropometric and cardiovascular measures in adults consuming cranberry juice cocktail.2 They analyzed data on 10,334 adults from the cross-sectional National Health and Nutrition Examination Survey (NHANES) combined 2005 to 2008 survey and determined consumers who drank an average of 14 fluid ounces of cranberry juice cocktail at least two consecutive days had significantly lower levels of C-reactive protein, a key marker of inflammation and heart disease.

Saw palmetto berries come from the Serenoa repens plant and have long been used and researched for benefits to prostate health, specifically in cases of benign prostatic hyperplasia (BPH). A late 2014 publication from Italian academic and hospital researchers reported a combination of saw palmetto, selenium, lycopene and tamsulosin (a drug known as Flomax) better improved IPSS (International Prostate Symptom Score, a measure of BPH) and Qmax (max flow rate) than any of the therapies alone.3 The randomized, double-blinded, double-dummy multicenter study involved 225 patients between the ages of 55 and 80 years old, who had lower urinary tract symptoms.

Flaxseed was also involved in recent research on BPH. Researchers from Frutarom, Vedic Lifesciences and Ruitenberg Ingredients published results in the

Journal of Medicinal Food at the end of 2014, detailing the effect of a lignan-rich extract of flaxseed hulls (as LinumLife EXTRA®, from

Frutarom) on BPH symptoms.4 The placebo-controlled, double-blind, randomized, parallel, multicenter study involved 60 BPH patients aged 45 to 75 years who had an American Urological Association Symptom Index (AUASI) score of 13 or higher. They were given either

a low (100 mg) or high (200 mg) dose of the flax phytoestrogen secoisolariciresinol diglucoside, or a placebo, for eight weeks. While the

flaxseed groups showed significant improvements to obstructive symptoms and management of irritable BPH symptoms, so did the placebo group.

From fruits to roots, research on rhizomes, bulbs and related botanicals recently generated positive results on a range of health conditions, from joint health to diabetes.

Curcumin, a compound from turmeric (Curcuma longa) root, has been red hot in the herbal marketplace, fueled partly by the growing volume of scientific evidence on its benefits to numerous health conditions including cancer, depression and Alzheimer’s disease. Research has focused on its antioxidant and anti-inflammatory properties. A December study published in Toxicology and Applied Pharmacology concluded curcumin protected pancreatic beta-cells in cellular stress-mediated diabetes.5 The Bose Institute, India, researchers explained curcumin lowered blood glucose, improved plasma insulin and inhibited oxidative stress markers, in addition to balancing inflammatory responses and limiting apoptosis pathways.


BOTANICALS RESEARCH

A four-month observational study reported in the last 2014 issue of European Review for Medical and Pharmacological Science compared a lecitihin delivery form of curcumin (as Meriva®, from Indena) combined with glucosamine to a combo of chondroitin and glucosamine in 124 patients with grade 1 to 2 osteoarthritis of the knee, which is marked by chronic inflammation and pain.6 The curcumin group had significantly higher WOMAC (Western Ontario and McMaster Universities Arthritis Index) and Karnofsky Index scores, performed significantly better in a treadmill walking distance test, and had a greater reduction in need for concomitant drugs and medical intervention. Researchers concluded Meriva with glucosamine results in faster onset of action and improved outcomes in OA patients, compared to glucosamine-chondroitin.

UCLA scientists think curcumin boosts DHA (docosahexaenoic acid) levels in the brain and may be beneficial in anxiety disorders.7 They reported curcumin increases the oft-noted as poor synthesis of DHA from alpha linolenic acid (ALA) and raises levels of particular enzymes found in the liver and brain that are involved in DHA synthesis. They noted curcumin and ALA treatment reduced anxiety-like behavior in rodents. The results suggested curcumin could help boost DHA levels and improve cognitive health in people who can’t or don’t eat fish or take marine-derived omega-3 products.

Fellow popular rhizome ginseng is praised as an adaptogen and has been researched for immune, blood sugar and cognitive benefits. However, the latest research on ginseng focused on joint health actions. A total ginsenoside-enriched fraction and a ginsenoside diol type-/F4-enriched fraction (GDF/F4) from Korean red ginseng (Panax ginseng) inhibited expression of matrix metalloproteinase-13 (MMP-13), an enzyme that participates in cartilage

Curcumin Drawing Pharma Attention

Drug discovery teams are exploring curcumin-related compounds in hopes of overcoming curcumin’s low absorption, rapid metabolism, poor chemical stability and fast systemic elimination. In a special issue of Molecules called “Curcumin, Inflammation, and Chronic Diseases: How are They Linked?” (Molecules 2015, 20(1), 249-292) researchers from Emory University, Atlanta, reported novel monocarbonyl analogs of curcumin (MACs) may be 10 to 20 times more potent than curcumin extract against cancer and inflammation. However, MACS have only been researched in vitro and in mice, not yet on large animals or humans.


BOTANICALS RESEARCH

degradation.8 In the study, a total ethanol extract and a ginsenoside diol-type-enriched fraction (from red ginseng leaf) failed to generate comparable results on MMP-13.

Ashwagandha (Withania somnifera) is also called Indian ginseng—although it is related to tomatoes and goji berries—and like true ginseng, it is a root-based botanical that has shown skeletal benefits. A January 2015 publication in Nutrition showed how ovariectomized rats (an osteoarthritis model) given withaferin A (from ashwagandha) experienced increased new bone formation and improved bone microarchitecture and biomechanical strength.9 Researchers noted the botanical compound acted on an inflammatory cytokine and a marker of bone turnover, in addition to supporting bone marrow cells and mineralization by inducing osteogenic gene expression.

A January 2015 study in Pharmaceutical Biology demonstrated how two dose levels (50 and 100 mg/kg/d) of ashwagandha root powder protected against pulmonary hypertension in rats by inhibiting inflammation, oxidative stress and endothelial dysfunction, as well as proliferative marker and apoptotic resistance in lungs.10 The Ayurvedic herbal staple significantly reduced right ventricular pressure and several markers of right ventricular hypertrophy.

The root vegetable garlic (Allium sativum)—a bit of a misnomer because it is a bulb, not a root—has its own big stack of research papers on its cardiovascular benefits, but two recent publications explore other known

pathways of garlic goodness. Research from Scotland appeared in the December issue of PLoS One, detailing an investigation into the

effects of aqueous garlic extract and its active compound allicin on Burkholderia cepacia complex (BCC), a phytopathogen for alliums such as garlic and a multiresistant and life-threatening

INSIDER Curcumin Resources

LEARN MORE about the health benefits, market data and manufacturing methods of curcumin in INSIDER’s Digital Issue: Curcumin Considerations. ➡

Discover the benefits of several branded curcumin ingredients in INSIDER’s Curcumin Battleground Digital Summit. ➡

A SPECIAL ALL-DIGITAL ISSUE VOLUME 4 ISSUE 13 $20.75 US July 2014

Curcumin CONSIDERATIONSFormulating and marketing the market’s

HOTTEST ANTIOXIDANT


BOTANICALS RESEARCH

bacteria for humans.11 Results suggested both allicin and allicin-containing garlic extract inhibit and kill BCC, which is common in hospital infections and can cause fatal lung infection in cystic fibrosis patients.

Building on allicin’s therapeutic potential in various areas of the body, Chinese researchers used an in vitro spinal cord injury model to study the protective effects of allicin on spinal cord neurons.12 They found allicin significantly inhibited loss of cell viability, apoptotic neuronal death and release of glutamate-induced lactate dehydrogenase (LDH), an enzyme released in damaged tissue and used as a marker for injury and disease. They noted reactive oxygen species (ROS) generation and lipid peroxidation were decreased, and antioxidant enzyme activities were preserved.

Above ground, ginkgo leaves have been a popular neuroprotective botanical, especially in the area of memory preservation. Recent research has examined ginkgo extract activities in other parts of the body. Researchers from Nanjing University of Chinese Medicine, Nanjing, studied Compound Ginkgo Biloba (CGB), a 1-to-1 preparation of Ginkgo biloba extract and Rosa roxburghii on endotoxin-induced intestinal permeability and inflammation in rats with chronic alcohol-induced liver injury.13 Results showed CGB downregulated genetic expression of several inflammatory agents, including TNF-alpha and TLR4, and upregulated tight junction proteins that help reverse gut barrier dysfunction.

Lithuanian researchers shed some light on ginkgo’s mechanism in mitochondria in a December 2014 paper in the Journal of Bioenergetics and Biomembranes.14 They explained how the standardized dry ginkgo leaf extract EGb761 uncoupled oxidative phosphorylation (the mitochondrial pathway involved in energy production) in rat heart mitochondria, but not in rat liver mitochondria. The extract also reduced hydrogen peroxide accumulation and pure cytochrome c, a marker and activator of apoptosis. The researchers concluded standardized dry ginkgo leaf extract may protect against cell death and preserve cellular functions in disease pathology.

Research on botanicals will continue to drive herbal product sales, which will stimulate further research to build the evidence for specific benefits and discover new areas of health plant compounds can potentially benefit. ■

Ginkgo leaves have been a popular neuroprotective botanical, especially in the area of memory preservation.


BOTANICALS RESEARCH

References1. Ulrey RK et al. “Cranberry proanthocyanidins have anti-biofilm properties against

Pseudomonas aeruginosa.” BMC Comp Alt Med. 2014; 14:499.

2. Duffey JK and Sutherland LA. “Adult consumers of cranberry juice cocktail have lower C-reactive protein levels compared with nonconsumers.” Nutrition Res. 2014 Dec 2; online ahead of print.

3. Albassam AA et al. “Inhibitory effect of six herbal extracts on CYP2C* enzyme activity in human liver microsomes. Xenobiuotica. 2014 Nov 28; online ahead of print.

4. Simons R et al. “Efficacy and Safety of a Flaxseed Hull Extract in the Symptomatic Management of Benign Prostatic Hyperplasia: A Parallel, Randomized, Double-Blind, Placebo-Controlled, Pilot Study.” J Med Food. 2014 Dec 29; online ahead of print.

5. Rashid K and Sil PC. “Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats.” Toxicol Appl Pharmacol. 2014 Dec 23; Online ahead of print.

6. Belcaro G et al. “Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study.” Eur Rev Med Pharmacol Sci. 2014 Dec;18(24):3959-63.

7. Wu A et al. “Curcumin boosts DHA in the brain: Implications for the prevention of anxiety disorders.” Biochim Biophys Acta. 2014 Dec 27; online ahead of print.

8. Lee JH et al. “Matrix metalloproteinase-13 downregulation and potential cartilage protective action of the Korean Red Ginseng preparation.” J Ginseng Res. 2014; 39(1):54-60.

9. Khedqikar V et al. “Preventive effects of withaferin A isolated from the leaves of an Indian medicinal plant Withania somnifera (L.): Comparisons with 17-β-estradiol and alendronate.” Nutrition. 2015; 31(1):205-213.

10. Kaur G et al. “Withania somnifera shows a protective effect in monocrotaline-induced pulmonary hypertension.” Pharm Biol. 2015; 53(1):147-57.

11. Wallock-Richards D et al. “Garlic Revisited: Antimicrobial Activity of Allicin-Containing Garlic Extracts against Burkholderia cepacia Complex.” PLoS One. 2014; 9(12): e112726.

12. Liu SG et al. “Allicin protects spinal cord neurons from glutamate-induced oxidative stress through regulating the heat shock protein 70/inducible nitric oxide synthase pathway.” Food & Function. 2015; 6(1):320-329.

13. Huanzhou L et al. “Effects of compound Ginkgo biloba on intestinal permeability in rats with alcohol-induced liver injury.” Food & Function. 2015 Nov 14; online ahead of print.

14. Baliutyte G et al. “Effects of standardized extract of Ginkgo biloba leaves EGb761 on mitochondrial functions: mechanism(s) of action and dependence on the source of mitochondria and respiratory substrate.” J Bioenergetic Biomembranes. 2014; 46(6):493-501.


BOTANICALS MARKET

IN THIS ISSUE

Botanicals Research p. 5

Botanical Drugs p. 15


For Entire Decade, U.S. Botanicals Market Grew

by Josh Long

It’s a good time to be a marketer of botanical and herbal dietary supplements, as data show.American consumers are increasingly

embracing natural products. In September, HerbalGram—the journal of the nonprofit American Botanical Council (ABC)—revealed in a market report that 2013 retail sales of herbal and botanical dietary supplements rose 7.9 percent to USD $6.032 billion, marking the 10th consecutive year that sales grew in the United States.

Herbs and botanicals achieved their biggest year of growth since the late 1990s, according to the 2013 market statistics, which were calculated by Nutrition Business Journal, and excluded sales of herbal teas, cosmetic products, and over the counter (OTC) and prescription medications. Herb retail sales decreased in 2002 and 2003 before increasing in 2004 for what would mark the first of 10 consecutive years of growth, according to the market report.

“Consumers continue to express strong demand for a wide variety of herbs, phytomedicines and other plant-based ingredients for their many health benefits,” Mark Blumenthal, HerbalGram editor in chief and ABC founder and executive director, said in a statement. “Over the past decade—even during the major economic downturn—retail sales statistics demonstrate the increasing level of interest and confidence that American consumers place in the herbal sector of the dietary supplement market.”

In the mainstream multi-outlet channel covering supermarkets, drugstores and mass market retailers, among other locations,

INSIDER's Take

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¾ The U.S. market for botanicals is thriving, as evidenced by 10 consecutive years of sales growth.

¾ Consumers are continuing to embrace mainstream herbs such as black cohosh, ginseng and St. John’s wort.

¾ Favorable publicity may have raised consumer awareness of the herbal and botanicals market, although it has also led to criticism of certain products.

2013 retail sales of herbal and botanical

dietary supplements rose

7.9%USD $6.032 billion,

marking the 10th consecutive year that sales grew in the

UNITED STATES

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to


BOTANICALS MARKET

2013 sales rose 9.4 percent to $994.2 million, HerbalGram reported, citing data compiled by two market research firms, SPINS and IRI. According to the market report, the five top-selling herbal supplements in the channel were: horehound ($106.9 million), an ingredient used in throat drops; yohimbe ($67.4 million), which is marketed for sexual enhancement and athletic performance products; cranberry ($48.8 million), long reputed to help prevent urinary tract infections; black cohosh ($46 million), which is consumed to manage menopausal symptoms; and senna ($32.3 million), a substance used as a stimulant laxative.

Sales growth in the mainstream multi-outlet channel “illustrates continued mainstream acceptance of popular herbs including … black cohosh, garlic, ginger, ginkgo, ginseng, milk thistle, saw palmetto, St. John’s wort and others,” HerbalGram stated. “Notable herbs and plant ingredients gaining popularity in this channel include … coconut oil, fenugreek, gymnema, maca and tribulus.”

In 2013, sales of herbal supplements in the natural channel ($320.7 million) and direct sales channel ($2.9 billion) rose 9.9 percent and 7.3 percent, respectively, according to the market report. Turmeric was the best-selling botanical in the natural channel, with 2013 sales reaching $21.3 million, a 26.2-percent increase over the previous year, HerbalGram reported.

Nearly one in four consumers believes taking herbal supplements is important to maintaining their health, according to the Natural Marketing Institute (NMI), a consulting and market research firm. Thirty-six million adults in the United States consume herbals, a 33-percent increase since 2011, NMI reported during a March 2014 American Herbal Products Association (AHPA) meeting.

What’s more, younger generations of Americans are more likely than their elders to view herbal supplements as safe and effective, NMI found. The market research firm also revealed that herbal users are fond of natural products, taking an average of 4.8 different supplements daily.

In recent years, favorable publicity may have raised consumer awareness of the herbal and botanicals market. Enter Mehmet Oz, M.D., the celebrity doctor and syndicated talk-show host. With nearly 3 million viewers daily, Dr. Oz has undoubtedly helped increase consumer interest in natural products. But some of his statements touting weight-loss products have also raised doubts, prompting members of the U.S. Senate to question him during a June 17, 2014 hearing on the deceptive advertising of such products before the Subcommittee on Consumer Protection, Product Safety and Insurance.

Sen. Claire McCaskill, the Missouri Democrat who chaired the subcommittee, referenced language used by Dr. Oz relative to weight-loss ingredients, such as

Turmeric was the best-selling

botanical in the natural

channel, with 2013 sales

reaching $21.3 million, a

26.2-percent increase over

the previous year.|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||


BOTANICALS MARKET

green coffee extract and the herbal supplement Garcinia cambogia, saying words like “magic” and “miracle” undermine his credibility, and put consumers at risk of deception and disappointment.

“Despite the continuing boom in the weight-loss industry, there exists very little scientific evidence that pills or supplements alone will cause sustained, meaningful weight loss,” Mary Engle, an FTC official, said in prepared testimony before the consumer protection subcommittee.

One executive in the botanicals market cited the importance of making claims that are substantiated by sound research to fuel sales.

“We think that clinical research and claims substantiation is what drives sales,” said Chase Shryoc, senior manager of business development with GE Nutrients Inc., whose supplement Testofen is a fenugreek extract.

George Pontiakos, president and CEO of BI Nutraceuticals, a supplier of botanical ingredients, identified three things that are driving consumer interest in botanicals: clean labels, safe and effective products, and products that provide multiple functions.

The company has observed a number of botanicals that are in high demand, including psyllium, guarana, cascara, chia seeds, ginseng, slippery elm, quinoa, goldenseal, black cohosh and cinnamon. Pontiakos noted that Native Americans used a number of the botanicals that are popular today, such as black cohosh, cascara and goldenseal.

More than 6,000 miles from BI’s office in Long Beach, California, the use of herbs dates back centuries and is associated with traditional Chinese medicine (TCM). The Asia Pacific region posted a compound annual growth rate (CAGR) of 9.6 percent from 2006 through 2011 to reach 1.2 million tons of botanicals in 2011, nearly double the use in North America, according to Diana Cowland, Euromonitor International health and wellness senior analyst.

“Application in Western Europe remains much lower, at 373,000 tons, as the use of botanicals in food and drink products within the EU is much more tightly regulated than in North America and Asia Pacific, for example,” Cowland wrote in a 2013 research note. “As such, consumers are less aware of their health-related benefits, and therefore less inclined to try the products.”

But in September, Persistence Market Research reported Europe has emerged in recent years as the biggest market for botanical supplements. A report by the market intelligence firm estimated the global botanical supplement market was valued at $54.6 billion in 2013 and will reach a value of $90.2 billion in 2020.

The forecast underscores that botanicals are increasingly appealing to consumers around the world and perhaps proof enough of their efficacy in promoting health. ■


IN THIS ISSUE

Botanicals Market p. 12

Galantamine p. 19


An Emerging Arena for Herbs: Botanical Drugs

by Robin C. Koon

F or centuries, people have used plants for healing. Plant-derived medicine products, as parts of foods, botanical potions, powders, poultices, etc., have been used with varying success to cure and

prevent diseases throughout history. A major change took place in the 19th century, when chemistry had advanced far enough to allow the extraction of active ingredients (and the isolation of active compounds) from herbs. This created the early drugs (such as cocaine, codeine, morphine, digitoxin, quinine and reserpine), which are still in use today. As a result, the use of chemical extracts started to displace herbs as medicine. During the 20th century, synthetic chemistry started to dominate the pharmaceutical industry, replacing natural products and extracts. Oftentimes, these new synthetic molecules have/had no connection to natural products. However, an estimated one-quarter of the prescription drugs sold in the United States, Canada and Europe contain active ingredients derived from plants.

Pharmacognosy is the study of medicines derived from natural sources. The term “pharmacognosy” derives from two Greek words, pharmakon or drug, and gnosis or knowledge (the chemistry and biology of natural products). It is the science that studies bioactive natural-derived substances (compounds, molecules, etc.) found in terrestrial and marine organisms (plants, animals or microbes) that produce medicines.

All plants produce chemical compounds (phytochemicals) as part of their normal metabolic actions. Some of these specialized compounds serve a specific function. For example, toxins deter predators, and colors or pheromones attract insects for pollination. Some of the organic chemical classes in plants are alkaloids, carotenoids, coumarins, flavones/flavonoids, glycosides, phenols, polypeptides, quinones, tannins, terpines/terpenoids, etc. Sometimes, these specialized compounds have

BOTANICAL DRUGS


BOTANICAL DRUGS

therapeutic effects for humans. Some examples of plant compounds that have been derived from or refined into drugs are:

NAME TYPE PLANT SOURCE

Aspirin Acetylsalicylic acid White willow bark

Atropine, hyoscyamine, scopolamine

Tropane alkaloid Nightshade (atropa belladonna)

Codeine, morphine, opiates Opiate alkaloids poppy Papaver spomniferum L.

Colchicine Isoquinoline alkaloid Colchicum autumnale

Cyclosporin-A Cyclic nonribosomal peptide Tolypocladium inflatum

Diosgenin, hecogenin, stigmasterol

Steroids Yam (dioscorea spp.)

Digoxin, digitoxin Steroidal glycosides Foxglove (digitalis spp.)

Erythromycin Metabolite Streptomyces erythreus

Lovastatin* Prodrug metabolite Red yeast rice

Nicotine Pyrrolidine alkaloid Nicotiana spp.

Paclitaxel (Taxol) Diterpenes Taxus brevifolia nutt.

Pilocarpine Imidazole alkaloid Physostigma venenosum balfor

Quinine Quinoloid alkaloid Cinchona spp.

Reserpine Indole alkaloid Rauwolfia serpentina l.

Senosides (A&B) Hydroxy-anthracene glycosides Cassia angustifolia vahl.

Vinblastine, vincristine Bis-indole alkaloid Catharanthus roseus L.

Yohimbine Indole alkaloid Apocynaceae rubiaceae spp.

*In 1998, FDA placed a ban on the sale of dietary supplements derived from red yeast rice (which naturally contains lovastatin), arguing that products containing prescription drug ingredient(s), thus require drug approval. Judge Dale A. Kimball of Federal District Court granted a motion by Pharmanex, that the agency’s ban was illegal under the Dietary Supplement Health and Education Act of 1994 (DSHEA) because the product was marketed as a dietary supplement, not a drug.

Botanical products are widely used by humans. In the United States, depending on labeling and intended use, a botanical can be a food, a dietary supplement and/or a drug. Drugs are products/compounds intended to diagnose, treat, prevent, mitigate or cure an abnormal medical condition(s). As such, drugs are regulated differentially than food, dietary supplements or cosmetics, which cannot make those types of disease claims. Generally, drugs are classified as either prescription or over the counter (OTC).

Most drug compounds are single active pharmaceutical ingredient (API) versus mixtures, and are compounds that are either plant-derived (chemically defined) or synthetically made. A few drug products are combinations of APIs.


BOTANICAL DRUGS

There is another category of drug that the FDA recognizes: “botanical drug.” Until 2004, when FDA issued its Draft Guidance on Botanical Drug Products, drug companies could still submit applications, but not know how FDA would perform the review process for the drug application. The 2004 guidance document established the first regulatory pathway for getting approval for a botanical drug.

A botanical drug, as defined by FDA in its draft guidance, is a botanical product that is prepared from a botanical drug substance, and is intended for use as a drug. A botanical drug is a mixture (polymolecular) of plant materials—that may include whole plant, plant parts (obtained from a plant, but no longer retains the structure of the plant and contains a complex mixture of compounds [e.g., fatty and essential oils, gums, resins and balms]), algae and macroscopic fungi. Excluded are materials from genetically modified botanicals species, fermentation products, highly isolated or purified compounds, or homeopathic ingredients, all of which are already regulated. Botanical drugs usually lack a distinct single active ingredient (API), with the drugs’ activity probably coming from several (multiple) active compounds.

Botanical drugs (all dosage forms) are regulated by FDA (section 505(b) of the Federal Food, Drug, and Cosmetic Act). A botanical drug product may be marketed in the United States as: 1 an OTC drug (under an OTC monograph, codified in 21 CFR parts 331 to 358), or 2 either prescription or OTC with an approved new drug application (NDA) or abbreviated new drug application (ANDA). Botanicals approved as a drug under the 1962 federal law—known as the Kefauver-Harris Amendments—requires drugs to be proven both safe and effective prior to being marketed in the United States. Botanicals are treated like any other new drug in order to gain full drug approval.

Getting botanical ingredients approved as a drug is somewhat new, and so far, only two botanicals have been approved by FDA. On Oct. 31, 2006, FDA approved the first botanical drug, Veregen®, a proprietary extract of green tea (camellia sinensis theaceae) for treating genital and perianal warts. FDA approved the second botanical NDA on Dec. 31, 2012, for Fulyzaq™ (crofelemer,

A botanical drug, as defined by FDA, is a botanical product that is prepared from a botanical drug substance, and is intended for use as a drug.


BOTANICAL DRUGS

an extract from the American croton tree), the first oral prescription botanical drug for the novel indication of HIV-associated diarrhea.

The evidence shows the difficulty in bringing a new drug to market in the United States. It now costs a reported USD $800 million to $1.3 billion to conduct the research and development needed to bring a new drug to the market, and the time can take 10 to 15 years for most new drugs to go from the laboratory to market.

Herbal drugs have several issues that are not applicable to synthetic drugs: 1 Herbal drugs are mixtures of many compounds, not a single API. Many

times, the active component(s) are unknown or difficult to determine. There are difficulties and challenges in determining or isolating each component of the complex mixtures that contributes to the products’ claimed effects.

2 Plant materials are naturally varied, and so are their compounds. Ensuring or keeping therapeutic consistency between each batch of material can be a difficult issue. The source and quality of the raw plant material are variable due to environment (where and when grown, soil, water, temperatures, etc.), the harvesting, drying, storage, transportation and processing methods used. These issues can cause a problem with reproducibility or standardization of the herb material being used, which makes it difficult to know whether one batch of an herb is equivalent to another. Having good control of the starting materials is essential, in order to ensure the reproducible quality of herbal medicinal products.

Once a botanical is being studied as a drug, under an investigational new drug (IND), or approved as a new drug in an NDA—its status as a dietary supplement does not change (unless the ingredient was not marketed as a supplement before the IND and subsequent NDA approval).

Though difficult, it is certainly not impossible for botanical companies to successfully complete FDA’s drug approval process. Currently, it is estimated that more than 100 drugs derived from a botanical source are currently under development by more than 80 companies. The global botanical drug market is expected to grow from $21.4 billion in 2011 to $26.6 billion in 2017, according to a report from BCC Research. ■

Robin Koon, executive vice president at Best Formulations, has more than 25 years of pharmaceutical experience in clinical pharmacy, as a retail drug chain executive, in managed-care and in manufacturing.


The Double Life of Galantamine by Corey Hilmas, M.D., Ph.D.

A few months back, after watching “Medicine Man,” the 1992 film about a research scientist working in the Amazon, I started reading articles about rediscovered plants that were thought to be extinct in the wild.

For instance, wild Arctostaphylos hookeri was lost for nearly 70 years until it was rediscovered by a botanist looking out onto a construction site near the Golden Gate Bridge.

Then, I began to consider the regulatory consequences for botanicals that result from the race to market. It made me think about many constituents of botanicals, highlighted in research from the world of pharmacognosy, which have been lost to the drug side. These botanicals are unavailable for use as dietary ingredients allowed in dietary supplements in the United States because they were branded as drug ingredients before they could be considered dietary ingredients, despite their history of use in food. But one botanical has a dual status as both a dietary and drug ingredient. While I would not say it is widely recognized in the dietary supplement industry, it does have a unique history and future.

Galantamine, or galanthamine as it was originally termed, is an alkaloid constituent contained in multiple members of the Amaryllidaceae family. The plants are often found native to Bulgaria, Russia, the Caucasus Mountains and portions of the Mediterranean, including Turkey. The use of galantamine had been established in Eastern Europe well before the last century, noted in several anecdotal reports to ease nerve pain and counter paralysis from poliomyelitis, but it would take another century to understand its crystalline structure and its lock-and-key interaction with an enzyme in the body.

The beginnings of galantamine read like a Cold War-era spy novel after the fall of Germany. World War II was as much an intellectual race to the finish among chemists to synthesize deadly chemicals that altered cholinergic neurotransmission, as it was a war fought on land, air and sea between the national

IN THIS ISSUE

Botanical Drugs p. 15

Business Takeaways p. 22


GALANTAMINE

Galantamine is an

ALKALOID CONSTITUENT

contained in multiple members of the

Amaryllidaceae family.

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GALANTAMINE

powers of the world. In the end, the Soviet Union was a step ahead in cholinesterase inhibitor pharmacology because its spoils from war included control of key chemical factories in East Germany, some of them dismantled and reassembled in the Soviet Union.

A Russian pharmacologist first isolated the plant alkaloid galantamine from Galanthus woronowii in the early 1950s and characterized its reversible physiological effects on muscle as an acetylcholinesterase inhibitor. The following year, the

chemical structure was elucidated by Proskurnina and Yakovleva. While the first patented synthetic pathway for galantamine was developed in 1996—two years after the passage of the U.S. Dietary Supplement Health and

Education Act of 1994 (DSHEA)—the alkaloid was being isolated from the snowdrop (Galanthus spp.), snowflake (Leucojum spp.) and daffodil (Narcissus spp.) many years earlier.

Galantamine received its second rebirth in the early 1990s in Baltimore. I witnessed a few of those years firsthand. Galantamine was found to act as an allosteric potentiating ligand of nicotinic receptors in the central nervous system. The short translation means it was found to have a second action in the body at cholinergic

synapses, one directed at proteins that form pores or channels in the membrane of neurons to allow the passage of certain ions for enhanced cell-to-cell communication. Researchers found the protein pores (ligand gated ion channels) acted

predominantly in the hippocampus, the center of the brain responsible for encoding memory. This established the first critical link between galantamine, memory

enhancement and neural protection from diseases that degrade memory over time.You might think big pharma beat the natural products industry

to the punch over galantamine in its race to market, altering its regulatory path away from dietary supplements. If it had not been for a lone new dietary ingredient (NDI) submission on galantamine to the fledgling NDI program at FDA in the early years after DSHEA, galantamine would have been lost to the drug world forever. The new drug application (NDA) on galantamine was filed only a few years later.

Today, galantamine is in very select company, as it holds distinction as both a dietary ingredient permitted for use in dietary supplements as well as a drug ingredient. While the sourcing of the ingredient may be different

Snowdrop (Galanthus spp.)

Snowflake (Leucojum spp.)

Daffodil (Narcissus spp.)

If it had not been for a

lone new dietary

ingredient (NDI)

submission,

galantamine would have

been lost to the drug

world forever.|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||


GALANTAMINE

depending on whether galantamine is used as a drug or supplement, supplements can use either the synthetic or natural-sourced version.

For galantamine, membership does not have its privileges. Despite being the first to market, galantamine supplements are unable to make the same claims as the drug. Galantamine, the drug ingredient, is approved for mild to moderate Alzheimer’s disease and other etiologies for memory impairment including vascular dementia, but galantamine, the dietary ingredient is not. Chemically and physiologically speaking, they are the same. Stated another way, FDA-approved therapeutic claims for galantamine, which may also have benefits on non-disease conditions to help with sleep and memory formation in healthy populations, are permitted only when the ingredient is used as a drug, but supplements are not able to carry those same disease claims. Perhaps it is time to make the case to change that limitation. Galantamine, with all its versatility, holds several possibilities for health and well-being, and perhaps 2015 is the year for clinical studies on this inconspicuous dietary ingredient.

This year, the Natural Products Association’s (NPA) Committee for Product Label and Integrity (ComPLI) will dig deeper and examine the issues related to ingredients such as galantamine, the claims those ingredients can make, their uses and FDA’s stance on those ingredients to ensure proper research and regulations are in place, industry rights are protected and consumers are being served in the best manner possible. ■

Corey Hilmas, M.D., Ph.D. is senior vice president, scientific and regulatory affairs, Natural Products Association.

Galantamine holds several possibilities for health, and perhaps 2015 is the year for clinical studies on this inconspicuous dietary ingredient.


Takeaways for Your Business

Botanicals are a vast and popular category of natural products, and the scientific exploration of botanicals and active plant compounds has steadily grown over the past few

decades. As herbal product sales continue upward trending, so has research on their many potential benefits to a wide variety of health concerns. Among the top-selling botanicals are cranberry, ginseng and curcumin.

The love of cranberry, from both consumers and researchers, has centered on its ability to limit bacterial adhesion, especially in the urinary tract. As study publications continue to strengthen the evidence on this effect, they also seek to clarify mechanisms against bacteria and find new areas of health where cranberries can be helpful.

Ginseng is a traditional herbal product touted for its adaptogenic properties that help many parts of the body. Most recently, a study published in the Journal of Ginseng Research detailed how Korean red ginseng in various extract and fraction forms can influence an enzyme that is involved in cartilage degradation.

Curcumin has sparked a variety of scientific exploration into new areas, as research has recently indicated the compound can boost levels of the omega-3 docosahexaenoic acid (DHA) in the brain, where it can positively affect cognitive health.

This research hasn’t gone unnoticed by companies looking to bring natural ingredients into pharmaceuticals. So far, only two botanicals have been approved by FDA. In 2006, FDA approved the first botanical drug, Veregen®, a proprietary green tea extract for treating genital and perianal warts. FDA approved the second botanical NDA in 2012, for Fulyzaq™ (crofelemer, an extract from the American croton tree), the first oral prescription botanical drug for the novel indication of HIV-associated diarrhea.

Currently, it is estimated that more than 100 drugs derived from a botanical source are currently under development by more than 80 companies. The global botanical drug market is expected to grow from $21.4 billion in 2011 to $26.6 billion in 2017, according to a report from BCC Research.

The supplement space is on a similar path. In September, HerbalGram revealed in a market report that 2013 retail sales of herbal and botanical dietary supplements rose 7.9 percent to USD $6.032 billion, marking the 10th consecutive year that sales grew in the United States. In fact, herbs and botanicals achieved their biggest year of growth since the late 1990s, according to the 2013 market statistics. ■

IN THIS ISSUE

Galantamine p. 19

INSIDER Contacts p. 23


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