OXFORD, Miss. - Establishing global quality and safety standards for materials used in the multibillion-dollar herbal industry is a priority for researchers in the University of Mississippi School of Pharmacy's National Center for Natural Products Research.

In this country, herbal products, or dietary supplements, are "not as tightly regulated as prescription drugs, so there is less assurance regarding their safety and their quality," said NCNPR Director Larry Walker.

Supplements are regulated by the U.S. Food and Drug Administration's Center for Food Safety and Applied Nutrition. If the FDA decides a product is mislabeled, adulterated or a health hazard, the agency can remove it from the market. But such violations are difficult to catch without industry standards and scientific methods to undergird research supporting these regulatory decisions.

Hammering home that point, Walker asks: "How do you determine that labels are accurate? Is a certain chemical constituent in a supplement a normal one or a contaminant? What methods are available to test these? If a natural constituent is thought to be harmful, how do you confirm it? If a certain constituent is harmful, what limits should be set for it?"

Answers to many of these questions require "developing new research methods,  identifying new constituents in herbal products or isolating them in pure form so they can be more rigorously studied," Walker said.  "That is where our work comes in."

For the past six years, NCNPR scientists have been testing, analyzing and authenticating botanical dietary supplements under a cooperative agreement with the FDA Center for Food Safety and Applied Nutrition.

"We are interested in research aimed at ensuring the quality and safety of supplements, and providing that information to the FDA, the botanical supplement community and the public," Walker said. "Other aspects of our work include basic research on natural products from many different sources - including plants, microbes and ocean life - and on translating our findings to pharmaceutical, agricultural or other applications."

Part of the center's work involves collecting, verifying and characterizing medicinal plants and extracts from them. Nearly 1,000 species have grown in the center's medicinal plant garden, which exchanges material and collaborates with more than 40 institutes worldwide.

"The university has earned its reputation for having one of the largest and best medicinal plant collections in the United States," said Aruna Weerasooriya, a plant taxonomist who manages the medicinal plant garden.

Obtaining plants or their seeds is a continual process, requiring international travel and transport. "There have been times when getting a species through customs was a problem," Weerasooriya said. "A few plants have perished en route to Mississippi."

Correct identification of each species is a critical first step to all other studies, such as determining which chemical compounds are responsible for a particular species' beneficial effects, how to grow it to optimize production of these compounds, and what the standards for purity and strength should be when the herbal product is sold to consumers. Some species - such as the fever-breaking Eupatorium perfoliatum L., commonly known as boneset - have been studied for introduction to Mississippi farmers as possible cash crops.

"We study their biology, best propagation and cultivation methods, seasonal chemical variations, and best harvesting and post-harvesting processes," Weerasooriya said. "After harvesting, plants are air-dried to preserve their chemical properties." Dried plants are ground into powder that NCNPR researchers extract and use in their studies.

Six years ago, David Pasco, a cellular and molecular biologist, and Ikhlas Khan, a pharmacognocist and director of NCNPR's FDA Program, discovered significant variations in products containing Echinacea, which are marketed as immune system boosters. Three species of the herb - E. angustifolia, E. purpurea and E. pallida - are used in the commercial preparations.

The amount of active compounds in those preparations can vary, depending upon which of the three species and which parts of the plants - leaves, stems or both - are used in the products. That's because each species and each part of the plant may contain different amounts of active compounds.

"From plant materials collected from 10 different sources around the country, we found up to a hundred fold difference in the materials' activities," Pasco said. "Differences in these materials, of course, imply the finished products would reflect the same variations."

It's variations like these that worry scientists, who hold strongly to the notion that research results must be replicated to be believed.

"If we don't use the same species or same plant materials in our studies, our research can never be repeated. And if we don't have standard materials for clinical trials, how can we determine if [a product or compound] has an efficacy? You really can't, which poses a big problem for researchers and consumers," Pasco said. "Standards are extremely important."

So, too, are the center's studies aimed at determining how ingredients in dietary supplements might cause harm to cells or organs in the body.

"Some problems with the safety of dietary supplements can stem from the inadvertent  use of the wrong plant species in their products," said center biochemist Shabana Khan.

Other problems can arise when contaminated plant materials are used. Some samples of ginseng, for example, contain fungicides and heavy metals such as lead, nickel and cadmium - which can be bad news for consumers if not monitored and limited. Other herbal products have been found to contain pollen, weeds and other biological contaminants.

So, in addition to screening botanicals for contaminants, NCNPR staff evaluate some botanicals for potential toxicity. Most of the work is done in vitro (in the test tube) using different human cell types cultured in the center's laboratories.

To determine whether a supplement causes, say, liver or kidney damage, extracts are dropped onto cultures containing human liver or human kidney cells, and cell damage or death is measured. After purification of the extracts, the process is repeated to focus on which compound in the extract kills the cells.

Efficacy, just how well a dietary supplement delivers the health benefits it's claimed to provide, "is not really a major issue for dietary supplements from a regulatory perspective," Walker said. That's because it's illegal to label, advertise or market supplements as disease treatments or preventatives.

"Under the law, these are 'drug' claims, and it's illegal for any supplement manufacturer to make these claims on its labels," Walker said.

Manufacturers may make some "structure-function" claims, such as "promotes healthy bones and joints" or "maintains a healthy immune system," he said. "But generally, the FDA's center regulating botanical supplements does not deal with how well supplements may work. Rather, they take seriously and as a top priority their safety mission - to first protect the public from potential harm, while not unduly restricting access to the supplements that are available according to law."

That doesn't mean NCNPR researchers don't have a stable of workhorse assays to determine the biological activity, or efficacy, of botanical compounds. They do, but they use the assays to find botanicals with potential to improve human health and to find leads to promising new medicines as part of their thriving drug discovery and development program.

They also determine how effectively botanical compounds are absorbed into the body by measuring how quickly they pass through cell membranes or single-cell layers in cultures with human intestinal cells.

"We can determine if a pure botanical extract would work better in the human body than when it has been compounded with other elements found in supplements," Shabana Khan said. In the lab, they can also study how supplements interact with other drugs taken at the same time by determining their interaction with drug-metabolizing enzymes.    

"This work is important to the health of our citizens," said UM Pharmacy Dean Barbara Wells. "We're providing the scientific underpinnings that allow development of standards and greater knowledge about how dietary supplements can be evaluated."

The center's work and that of others is paying off.

"Many quality manufacturers and distributors understand the importance of this work and are taking it upon themselves to develop standards, even in cases where it may not be compulsory," Walker said. "And the industry as a whole, via trade associations and the like, is trying to elevate the general quality and safety of herbal products."

The FDA chose to partner with NCNPR in this effort because the center is renowned for its work with biologically active plant materials.

"For more than a decade, the center has been an international leader in understanding the chemistry and biology of medicinal plants and their impact on human health," said UM chief research officer Alice Clark.

For more information about the center and the FDA partnership on botanicals, go to http://www.olemiss.edu/depts/pharmacy/ncnpr.

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