Antioxidants are entering a new era of product performance.

By Ronald Prior, PhD, & Boxin Ou, PhD, David Bell, MBA, Qiuyan Zhao, MD, MBA, & HuiLin Wei, MD, PhD, Brunswick Laboratories


Antioxidants are growing up. They have emerged from their adolescence into the prime of maturity. In doing so, they have proven themselves to be versatile performers. In fact, these natural product compounds traditionally referred to as “antioxidants” may deserve a new name—”antiAGEnts.”

In the past decade, antioxidants have captured the consumer imagination—for the most part, for the better. They have become a part of the consumer vocabulary and have helped shape the landscape of nutrition products, from conventional supplements to specialty foods to cosmetics. During this time, antioxidant research has been robust. Central to the findings are: (1) that phyto-compounds traditionally called “antioxidants” demonstrate diverse characteristics; and (2) that “antioxidants” are implicated in a complex array of interconnected mechanisms in vivo.

The diversification of antioxidants’ role has important implications for natural products and the varied forms they take in the anti-aging marketplace.

The New Science of Antioxidants

There is continued interest in and questions regarding the antioxidant capacity of the diet and in vivo antioxidant status and effects on health outcomes. There is increasing evidence that the postprandial (after meal) state is an important contributing factor to chronic disease. A decrease in plasma antioxidant capacity has been observed following a meal containing macronutrients but no sources of antioxidants. The role of fruit and vegetable phenolic compounds to protect health and lower disease risk through their actions in mitigating fed-state metabolic and oxidative stressors is of interest.

Berries such as blueberries, grapes and strawberries have been shown to reduce postprandial oxidative stress. More research is needed in this area, but data from several studies

summarized by Dr. Burton-Freeman suggest that consuming phenolic-rich fruits increases the antioxidant capacity of the blood. And when they are consumed with high fat and carbohydrate “pro-oxidant and pro-inflammatory” meals, they may counterbalance their negative effects. Given the content and availability of fat and carbohydrates in the Western diet, regular consumption of phenolic-rich foods, particularly in conjunction with meals, appears to be a prudent strategy to maintain oxidative balance and health.

It is becoming increasingly apparent that phenolic-rich foods may impact health outcomes through other mechanisms in addition to strictly antioxidant effects. Studies suggest that oxidative stress and systemic inflammation are involved in the pathogenesis of ischemic stroke and consuming a diet with a high total antioxidant capacity has been related to reduced inflammation, along with increased circulating antioxidants. In a cross-sectional and randomized intervention study of 41,620 men and women, a diet rich in total antioxidant capacity was associated with a reduction in incidence of ischemic stroke and to a lesser extent in all types of stroke. In another study, positive associations were observed between dietary antioxidant capacity and adiponectin concentration and a negative relationship with inflammatory markers. As a result, an adiponectin-mediated route through which antioxidant-rich foods exert beneficial effects against inflammation and cardiovascular diseases can be hypothesized.

Consumption of a Mediterranean diet, especially rich in virgin olive oil, has also been associated with higher levels of plasma antioxidant capacity. In addition, plasma total antioxidant capacity may lead to a reduction in body weight after three years of intervention in a high cardiovascular risk population.

In another study, a group of patients with Type 2 diabetes was given a polyphenol-rich antioxidant supplement, and a decrease in LDL and an increase in HDL was observed. In addition, a byproduct of lipid peroxidation (plasma MDA) was decreased in the study group compared to the placebo group, and an increase in antioxidant defense was observed based upon increases in total plasma GSH and antioxidant capacity. These observations indicated that the polyphenol-rich antioxidant supplement may have been important in antagonizing effects on oxidative stress and lipid peroxidation in patients with Type 2 diabetes and might be beneficial in preventing cardiovascular complications.

Based on positive associations observed for total fruit and vegetable intakes and what was termed total antioxidant performance, Talegawkar et. al. suggested that it might be prudent to focus on increasing consumption of fruit, vegetables, nuts and seeds to increase total antioxidant capacity.

In this vein, accurately testing the antioxidant level in natural products and ex vivo samples remains an important task, which is why the Oxygen Radical Absorbance Capacity (ORAC) method remains relevant. And here’s why: (1) ORAC is an established standard that already plays a valuable role in the dietary supplement and functional food industries; (2) significant improvements have been made to the method; and (3) there appears to be a vital link between ORAC level and bioassay efficacy markers.

The ORAC Method Today

Briefly, ORAC was developed as an analytical tool for estimating the antioxidant capacity of substances, with an obvious application to natural products. It was an important advancement in commercially available analysis and has become a de facto standard in the natural products industry. Let’s consider some important facts:

• From the beginning, the ORAC method was considered a starting spot—not a definitive endpoint—for comprehensive antioxidant analysis.

• The original ORAC method is not a universal standard—it favors certain antioxidant substances over others (e.g., anthocyanins over carotenoids) due to the use of only one free radical source (peroxyl radical), which was chosen initially because it is the most common radical source found in the human body.

• There now exists a complementary suite of assays based on a unified ORAC chemistry that broadens the analytical scope of antioxidant testing.

This evolution process has resulted in the Total ORAC suite. It expands the ORAC platform to measure antioxidant capacity against five primary reactive oxygen species (commonly referred to as radicals)—peroxyl, hydroxyl, peroxynitrite, superoxide anion and singlet oxygen.

While Total ORAC is subject to some of the same limitations as the original ORAC method, it substantially improves broad-spectrum antioxidant analysis. It also gives evidence of the diverse antioxidant potential of natural products against radicals other than peroxyl. In some instances this potential may be specialized (e.g., carotenoids vs. singlet oxygen); in other cases, there is balanced antioxidant performance against multiple radicals. Compounds such as resveratrol and standardized ingredients such as green tea extract exhibit significant broad-spectrum antioxidant capacity.

The significance of Total ORAC is that while these primary radicals may all broadly contribute to the same outcomes—oxidative damage and corresponding disease states—they have unique characteristics that need to be addressed. Like position players on a sports team, antioxidant substances have different skill sets. And it is meaningful and valuable to know how antioxidants will perform against different opponents.

Turmeric (Curcuma longa Linn) and Curcumin

While some complementary and alternative techniques have been studied scientifically, high- quality data regarding safety, effectiveness, and mechanism of action are limited or controversial for most therapies. Whenever possible, it is recommended that practitioners be licensed by a recognized professional organization that adheres to clearly published standards.

Background
• The rhizome (root) of turmeric (Curcuma longa Linn.) has long been used in traditional Chinese medicine to treat gastrointestinal upset, arthritic pain, and "low energy." Laboratory and animal research has demonstrated anti-inflammatory, antioxidant, and anti-cancer properties of turmeric and its constituent curcumin. Preliminary human evidence, albeit poor quality, suggests possible efficacy in the management of dyspepsia (heartburn), hyperlipidemia (high cholesterol), and scabies (when used on the skin).

Scientific Evidence
Uses
These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Grade*
Antioxidant
Oxidative stress has been shown to result in abnormal functioning of the cells that line the inner surface of arteries and veins. Given the potential antioxidant effects of curcumin, one clinical trial examined the role of NCB-02, which is a standardized preparation of curcuminoids, on functioning of these cells and markers of this process in patients with type 2 diabetes and demonstrated positive results. More well-designed clinical trials are needed before a recommendation can be made.

Blood clot prevention
Early research suggests that turmeric may prevent the formation of blood clots. However, more research is needed before turmeric can be recommended for these conditions.

Cancer
Several early animal and laboratory studies report anti-cancer (colon, skin, breast)
properties of curcumin. Many mechanisms have been considered, including antioxidant activity, anti-angiogenesis (prevention of new blood vessel growth), and direct effects on cancer cells. Currently it remains unclear if turmeric or curcumin has a role in preventing or treating human cancers. There are several ongoing studies in this area.


Cognitive functio

n
Curcumin has been shown to have antioxidant and anti-inflammatory properties and to reduce beta-amyloid and plaque burden in lab studies. However, there is currently not enough evidence to suggest the use of curcumin for cognitive performance.

Dyspepsia (heartburn)
Turmeric has been traditionally used to treat stomach problems (such as indigestion from a fatty meal). There is preliminary evidence that turmeric may offer some relief from these stomach problems. However, at high doses or with prolonged use, turmeric may actually irritate or upset the stomach. Reliable human research is necessary before a recommendation can be made.

Gallstone prevention/bile flow stimulant
It has been said that there are fewer people with gallstones in India, which is sometimes credited to turmeric in the diet. Early studies report that curcumin, a chemical in turmeric, may decrease the occurrence of gallstones. However, reliable human studies are lacking in this area. The use of turmeric may be inadvisable in patients with active gallstones.

High cholesterol
Early studies suggest that turmeric may lower levels of low-density lipoprotein ("bad cholesterol") and total cholesterol in the blood. Better human studies are needed before a recommendation can be made.

HIV/AIDS
Several laboratory studies suggest that curcumin, a component of turmeric, may have activity against HIV. However, reliable human studies are lacking in this area.

Inflammation
Laboratory and animal studies show anti-inflammatory activity of turmeric and its
constituent curcumin. Reliable human research is lacking.

Irritable bowel syndrome (IBS)
Irritable bowel syndrome (IBS) is a common functional disorder for which there are limited reliable medical treatments. One study investigated the effects of Curcuma xanthorriza on IBS and found that treatment did not show any therapeutic benefit over placebo. More studies are needed to verify these findings.

Liver protection
In traditional Indian Ayurvedic medicine, turmeric has been used to tone the liver. Early research suggests that turmeric may have a protective effect on the liver, but more research is needed before any recommendations can be made.

Oral leukoplakia
Results from lab and animal studies suggest turmeric may have anticancer effects. Large, well-designed human studies are needed before a recommendation can be made.

Osteoarthritis
Turmeric has been used historically to treat rheumatic conditions. Laboratory and animal studies show anti-inflammatory activity of turmeric and its constituent curcumin, which may be beneficial in people with osteoarthritis. Reliable human research is lacking.

Peptic ulcer disease (stomach ulcer)
Turmeric has been used historically to treat stomach and duodenal ulcers. However, at high doses or with prolonged use, turmeric may actually further irritate or upset the stomach. Currently, there is not enough human evidence to make a firm recommendation.

Rheumatoid arthritis
Turmeric has been used historically to treat rheumatic conditions and based on animal research may reduce inflammation. Reliable human studies are necessary before a recommendation can be made in this area.

Scabies
Historically, turmeric has been used on the skin to treat chronic skin ulcers and scabies. It has also been used in combination with the leaves of the herb Azadirachta indica ADR or "neem." More research is necessary before a firm recommendation can be made.

Uveitis (eye inflammation)
Laboratory and animal studies show anti-inflammatory activity of turmeric and its
constituent curcumin. A poorly designed human study suggests a possible benefit of
curcumin in the treatment of uveitis. Reliable human research is necessary before a firm conclusion can be drawn.

Viral infection
Evidence suggests that turmeric may help treat viral infections. However, there is not enough human evidence in this area. Well-designed trials are needed to determine if these claims are true.

Tradition/Theory
The below uses are based on tradition, scientific theories, or limited research. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider. There may be other proposed uses that are not listed below.

• Abdominal bloating, Alzheimer's disease, antibacterial, antifungal, antimicrobial,
antispasmodic, anti-venom, appetite stimulant, asthma, boils, breast milk stimulant,
bruises, cataracts, chemoprotective, colic, constipation, contraception, cough, cystic
fibrosis, diabetes, diarrhea, dizziness, dyspepsia, epilepsy, fever, flavoring agent, gas,
gonorrhea, heart damage from doxorubicin (Adriamycin®, Doxil®), Helicobacter pylori infection, hepatitis, high blood pressure, histological dye, human papillomavirus (HPV), hypoglycemic agent (blood sugar lowering), infections (methicillin-resistant Staphylococcus aureus), insect bites, insect repellent, intestinal worms, jaundice, kidney disease, kidney stones, leprosy, liver damage from toxins/drugs, male fertility, menstrual pain, menstrual period problems/lack of menstrual period, multidrug resistance, muscle ache, nutritional support, neurodegenerative disorders, pain, parasites, rheumatic disorders, ringworm, runny nose, scarring, scleroderma, sepsis, skin disorders, stroke prevention, toxicity, urinary disorders, weight reduction, wound healing.

Dosing
The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (over 18 years old)
• Doses used range from 450 milligrams of curcumin capsules to 3 grams of turmeric root daily, divided into several doses, taken by mouth. As a tea, 1 to 1.5 grams of dried root may be steeped in 150 milliliters of water for 15 minutes and taken twice daily. Average dietary intake of turmeric in the Indian population may range between 2 to 2.5 grams, corresponding to 60 to 200 milligrams of curcumin daily. A dose of 0.6 milliliters of turmeric oil has been taken three times daily for one month and a dose of 1 milliliter in three divided doses has been taken for two months.
• One reported method for treating scabies is to cover affected areas once daily with a paste consisting of a 4:1 mixture of Azadirachta indica ADR ("neem") to turmeric, for up to 15 days. Scabies should be treated under the supervision of a qualified healthcare professional.
Children (under 18 years old)
• There is no proven or safe medicinal dose of turmeric in children.

Safety
The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always
read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies
• Allergic reactions to turmeric may occur, including contact dermatitis (an itchy rash) after
skin or scalp exposure. People with allergies to plants in the Curcuma genus are more likely to have an allergic reaction to turmeric. Use cautiously in patients allergic to turmeric or any of its constituents (including curcumin), to yellow food colorings, or to plants in the Zingiberaceae (ginger) family.

Side Effects and Warnings
• Turmeric may cause an upset stomach, especially in high doses or if given over a long period of time. Heartburn has been reported in patients being treated for stomach ulcers. Since turmeric is sometimes used for the treatment of heartburn or ulcers, caution may be necessary in some patients. Nausea and diarrhea have also been reported.
• Based on laboratory and animal studies, turmeric may increase the risk of bleeding. Caution is advised in patients with bleeding disorders or taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary. Turmeric should be stopped prior to scheduled surgery.
• Limited animal studies show that a component of turmeric, curcumin, may increase liver function tests. However, one human study reports that turmeric has no effect on these tests. Turmeric or curcumin may cause gallbladder squeezing (contraction) and may not be advised in patients with gallstones. In animal studies, hair loss (alopecia) and lowering of blood pressure have been reported. In theory, turmeric may weaken the immune system and should be used cautiously in patients with immune system deficiencies.
• Turmeric should be used with caution in people with diabetes or hypoglycemia or people taking drugs or supplements that lower blood sugar.
• Turmeric may increase the risk of kidney stone formation in people prone to kidney stones.
Pregnancy and Breastfeeding
• Historically, turmeric has been considered safe when used as a spice in foods during pregnancy and breastfeeding. However, turmeric has been found to cause uterine stimulation and to stimulate menstrual flow and caution is therefore warranted during pregnancy. Animal studies have not found turmeric taken by mouth to cause abnormal fetal development.

Interactions
Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.
Interactions with Drugs
• Based on laboratory and animal studies, turmeric may inhibit platelets in the blood and increase the risk of bleeding caused by other drugs. Some examples include aspirin, anticoagulants ("blood thinners") such as warfarin (Coumadin®) or heparin, anti-platelet drugs such as clopidogrel (Plavix®), and non-steroidal anti-inflammatory drugs such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®).
• Based on animal data, turmeric may lower blood sugar and therefore may have additive effects with diabetes medications.
• In animals, turmeric protects against stomach ulcers caused by non-steroidal anti-
inflammatory drugs (NSAIDs) such as indomethacin (Indocin®) and against heart
damage caused by the chemotherapy drug doxorubicin (Adriamycin®).
• Turmeric may lower blood pressure levels and may have an additive effect if taken with drugs that also lower blood pressure.
• Turmeric may lower blood levels of low-density lipoprotein (LDL or "bad" cholesterol) and increase high-density lipoprotein (HDL or "good" cholesterol). Thus, turmeric may increase the effects of cholesterol-lowering drugs such as lovastatin (Mevacor®) or atorvastatin (Lipitor®).
• Based on animal studies, turmeric may interfere with the way the body processes certain drugs using the liver's "cytochrome P450" enzyme system. As a result, the levels of these drugs may be increased in the blood and may cause increased effects or potentially serious adverse reactions. Patients using any medications should check the package insert and speak with a healthcare professional or pharmacist about possible interactions.
• When taken with indomethacin or reserpine, turmeric may help reduce the number of stomach and intestinal ulcers normally caused by these drugs. However, when taken in larger doses or when used for long periods of time, turmeric itself can cause ulcers. Interactions with Herbs and Dietary Supplements
• Based on animal studies, turmeric may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba, some cases with garlic, and fewer cases with saw palmetto.
• Based on animal data, turmeric may lower blood sugar. Individuals taking other herbs or supplements or diabetes medications should speak with a healthcare professional before starting turmeric.
• Turmeric may lower blood levels of low-density lipoprotein (LDL or "bad" cholesterol) and increase high-density lipoprotein (HDL or "good" cholesterol). Thus, turmeric may increase the effects of cholesterol-lowering herbs or supplements such as fish oil, garlic, guggul, or niacin.
• Based on animal studies, turmeric may interfere with the way the body processes certain herbs or supplements using the liver's "cytochrome P450" enzyme system. As a result, the levels of other herbs or supplements may become too high in the blood. It may also alter the effects that other herbs or supplements possibly have on the P450 system.
• Turmeric may lower blood pressure and may therefore have an additive effect if taken with herbs that also lower blood pressure.


• This information is based on a systematic review of scientific literature edited and peer- reviewed by contributors to the Natural Standard Research Collaboration
(www.naturalstandard.com).
References
Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about
alternative and complementary therapies on the professional level, go to
www.naturalstandard.com.

Broccoli sprouts: Cancer

Source: Nutr Cancer, February 2011;63(2):196-201.

Research: Sulforaphane (SF) is a chemopreventive isothiocyanate (ITC) derived from the myrosinase-catalyzed hydrolysis of glucoraphanin, a thioglucoside present in broccoli. Broccoli supplements often contain glucoraphanin but lack myrosinase, putting in question their ability to provide dietary SF. This study compared the relative absorption of SF from air-dried broccoli sprouts rich in myrosinase and a glucoraphanin-rich broccoli powder lacking myrosinase, individually and in combination. Subjects (n = 4) each consumed 4 meals consisting of dry cereal and yogurt with 2 g sprouts, 2 g powder, both or neither. Blood and urine were analyzed for SF metabolites.

Results: The 24-hour urinary SF recovery was 74%, 49% and 19% of the dose ingested from broccoli sprouts, combination and broccoli powder meals, respectively. Urinary and plasma ITC appearance was delayed from the broccoli powder compared to the sprouts and combination. A liver function panel indicated no toxicity from any treatment at 24 hours. These data indicate a delayed appearance in plasma and urine of SF from the broccoli powder relative to SF from myrosinase-rich sprouts. Combining broccoli sprouts with the broccoli powder enhanced SF absorption from broccoli powder, offering the potential for development of foods that modify the health impact of broccoli products.

PMS - B Vitamin-rich food

Source: Am J Clin Nutr, February 23, 2011;[Epub ahead of print]

Research: Thiamine, riboflavin, niacin, vitamin B-6, folate and vitamin B-12 are required to synthesize neurotransmitters that are potentially involved in the pathophysiology of premenstrual syndrome (PMS). In this study, researchers set out to evaluate whether B vitamin intake—from food sources and supplements—is associated with the initial development of PMS. They conducted a case-control study nested within the Nurses’ Health Study II cohort among participants who were free of PMS at baseline (1991). After 10 years of follow up, 1057 women were confirmed as cases and 1968 were confirmed as controls. Dietary information was collected in 1991, 1995 and 1999 by using food-frequency questionnaires.

Results: Intakes of thiamine and riboflavin from food sources were each inversely associated with incident PMS. For example, women in the highest quintile of riboflavin intake 2-4 years before the diagnosis year had a 35% lower risk of developing PMS than did those in the lowest quintile. However, there were no significant associations between incident PMS and dietary intakes of niacin, vitamin B-6, folate, and vitamin B-12. Additionally, intake of B vitamins from supplements was not associated with a lower risk of PMS.

Prostate Cancer - Vitamin E, Soy and Selenium

Source:J Clin Oncol, May 2, 2011. [Epub ahead of print].

Research: High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa) and preclinical evidence suggests vitamin E, selenium and soy protein may prevent the progression of HGPIN to PCa. This hypothesis was tested among 300 men in a randomized phase III double-blind study of daily soy (40 grams), vitamin E (800 IUs) and selenium (200 μg) consumption versus placebo. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24 and 36 months post-randomization.

Results: For all patients, the median age was 63 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26% of patients. Gleason score distribution was similar in both groups, with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% vs. 17%) among men receiving micronutrients. According to researchers, this trial does not support the hypothesis that combination vitamin E, selenium and soy prevents progression from HGPIN to PCa.

Olive Oil and Stroke

Source: Neurology, June 15, 2011;[Epub ahead of print].

Research: Among participants from the Three-City Study with no history of stroke at baseline, researchers examined the association between olive oil consumption (main sample, n=7625) or plasma oleic acid (secondary sample, n=1245) and incidence of stroke (median follow-up 5.25 years), ascertained according to a diagnosis validated by an expert committee.

Results: In the main sample, 148 incident strokes occurred. After adjustment for socio-demographic and dietary variables, physical activity, body mass index, and risk factors for stroke, a lower incidence for stroke with higher olive oil use was observed. Compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke. In the secondary sample, 27 incident strokes occurred. After full adjustment, higher plasma oleic acid was associated with lower stroke incidence. Compared to those in the first tertile, participants in the third tertile of plasma oleic acid had a 73% reduction of stroke risk.

Herbs & Botanicals Market - Brazil

By Julie Dennis
otanical sales continue their gradual ascent in regions across the globe regardless, or perhaps because of, economic woes.

“Part of it is economics; you can’t afford to get sick,” said George Pontiakos, president and CEO, BI Nutraceuticals, Long Beach, CA. “The trusted, consultative, medical resource is not out there; your family doctor is not there anymore and people are recognizing they have to take their health into their own hands.”

It’s not all economics, though. Many people simply want to live healthier lives and botanicals are simply part of that goal. “Consumers continue to demonstrate their interest in and demand for natural ways to improve their health,” said Mark Blumenthal, founder and executive director, American Botanical Council (ABC), Austin, TX, and editor of HerbalGram and HerbClip.

Increasing demand for botanical remedies is both a national, and international, trend. In fact, the global herbal supplement and remedies market is expected to reach $93 billion by 2015, according to a new report by San Jose, CA-based Global Industry Analysts, Inc.

Brazil: Botanical Climate

Another notable botanical market is Brazil, as regulations continue to change and opportunity continues to knock. The economy is relatively stable, wages are rising for many, and education and consumer demand for dietary supplements are increasing.

“Brazil is going through a period of rapid growth, and consumption of health and beauty products is growing accordingly,” said Paul Altaffer, vice president of business and product development, RFI Ingredients, LLC, Blauvelt, NY. “Supplement sales are soaring as consumers are buying international and domestic branded products. As the economy grows so does income—and Brazil’s income inequality gap is narrowing, meaning more Brazilians can afford what a short period of time ago were considered luxury goods.”

Brazil shares the same health concerns experienced by most industrialized nations, including obesity/overweight, lack of energy, stress, heart issues and immunity, according to Mr. Altaffer.

The aging population in Brazil, similar to the EU and the U.S., is also a driving force behind consumer spending. In fact, consumers over age 60 are estimated to contribute about 13% of Brazil’s total income, according to a Euromonitor report.

Addressing these concerns are some of the top-selling botanicals, including guarana, mate, acerola, acai, camu camu, cha de bugre, catuaba and boldo, Mr. Altaffer said.

But with opportunity also comes challenges, especially as regulations continue to evolve and thwart more dramatic sales increases. One factor contributing to this slowing pace is the group of South American countries currently banding together to develop uniform regulations.

Countries involved in this process include Brazil, Argentina, Paraguay, Chile and Uruguay. Consensus and stability are still elusive as these diverse countries attempt to transform the regulatory landscape.

“The system is quite bureaucratic. It becomes more complex as a result of Brazil’s (primarily) effort to come up with a common regulatory environment (similar to CODEX in Europe),” Mr. Altaffer explained. Needless to say, the pace of adopting new regulations has been slow.

The emerging regulations are intended to bring Brazil “in line with U.S. and European regulatory frameworks. Brazil emulates the Europeans. As a result, supplements must all be registered with ANVISA (Brazil’s regulatory agency for health products and services), demonstrating safety/toxicity, efficacy and so on,” Mr. Altaffer added.

Botanical Drug Update

The botanical drug industry is steadily growing despite high costs of approval.

Over the past decade, a new U.S. botanical drug industry has been steadily growing, according to Freddie Ann Hoffman, MD, CEO and founding member of the Washington, D.C.-based consulting firm HeteroGeneity, LLC, which focuses on the development of complex, heterogeneous products, such as botanicals, for the U.S. market.

Unlike dietary supplements, products classified as botanical drugs are intended for use in the diagnosis, mitigation, treatment, cure or prevention of disease, and also affect the structure or function of the body, Ms. Hoffman explained. In the U.S., these disease claims classify the product as a drug under the federal Food, Drug and Cosmetic Act.

Any product not already approved as a “drug” must be approved under a New Drug Application (NDA) with FDA prior to being marketed.

To study a new drug, the drug’s sponsor must first file an Investigational New Drug (IND) application with the FDA. This allows the drug to be studied in humans to obtain the safety and efficacy data required for U.S. drug approval.

Furthermore, the product must be manufactured under strict conditions with a high-level of reproducibility and documentation, including the collection of nonclinical, and clinical data, using rigorous experimental designs, Ms. Hoffman said.

Regardless of the high cost of pursuing a drug approval, for many manufacturers the appeal outweighs the price. There are approximately “500 INDs for botanical drugs that have been submitted to FDA in various stages of development. Many of these future drugs offer novel mechanisms of action,” Ms. Hoffman noted.

While not a “botanical,” FDA approved a complex natural drug from an omega 3 fatty acid rich fish oil in November 2004. This drug is now marketed as Lovaza (GlaxoSmithKline), and according to IMS Health has had annual sales exceeding $1 billion dollars since 2009.

In October 2006, the green tea extract Veregen was also approved as a “new” drug, and is now a prescription drug approved for topical use to treat genital warts. Further, several older botanical ingredients, such as psyllium, are regulated as both “food” and “drug” ingredients.

The potential benefits for the manufacturer pursuing a drug classification include significantly stronger labeling, such as direct clinical indications and promotional claims, warnings, precautions and contraindications for clinical use, and therefore “buy-in” by U.S. healthcare professionals—with possible reimbursement for prescription drugs. There is also significant protection of proprietary information, including trade secrets—i.e., competitors cannot “borrow” science, unless the second drug is a “generic equivalent.”

“To claim ‘generic equivalency,’ the active(s) from both drugs must be administered to human subjects and demonstrate comparable absorption and distribution patterns, in conformance with standardized ‘bioequivalence’ testing procedures,” Ms. Hoffman explained.

Also, approved NDAs are given a period of exclusive marketing rights wherein FDA is prohibited from accepting another NDA submission for an identical product.

“There are many diseases and conditions that do not respond to a single drug. Cancer is one of these, as is HIV infection and other infectious and inflammatory conditions. The standard of care for these conditions is to use a ‘cocktail’ of drugs,” said Ms. Hoffman. “Because botanicals are such complex products they may be able to hit multiple targets to prevent the resistance formed by malignant cells and some infectious agents, for example.”

“Nature is a fantastic biochemist, which offers infinite possibilities for drug exploration,” she said, adding that if proven to work under strict U.S. drug law, “the future for complex drugs in the U.S. is wide open and bright.” —JD