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From the potion to the pill

Yale Medicine Magazine, 2007 - Spring


In traditional Chinese medicine, the herb yarrow is used to treat the common cold, colic, indigestion and toothache.By characterizing and quantifying the active ingredients in traditional Chinese herbal remedies, Yale scientists hope to improve treatment and reduce toxicity for cancer patients.

Western physicians, who demand clinical proof of a drug’s efficacy, and proponents of alternative remedies, who point to anecdotal evidence that their products work, have carved out distinct but neighboring territories in the world of medicine. Although the inhabitants of these territories have often regarded each other with suspicion, their borders have become increasingly porous. According to a 2004 survey by the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (NIH), 36 percent of Americans 18 or older have tried an alternative remedy. That survey also found that 26 percent of the respondents used alternative treatments based on a recommendation from a mainstream medical practitioner.

This wary and shifting relationship stems in part from differing world views. Practitioners of traditional or alternative medicine take a more holistic view of healing than their mainstream counterparts. And mainstream physicians see a lack of scientific rigor in published evaluations of traditional medicines whose recipes have been handed down over generations. Furthermore, how does a physician calculate a reliable dosage of a medicine that’s brewed in a tea and whose chemical makeup depends on how much water and how many leaves are used, where the plants were grown, when they were harvested and how much it rained that season?

Now Yale scientists are attempting to bring traditional Chinese medicine into the mainstream. Working with two companies in New Haven and Taiwan, they have brought precision and consistency to a traditional Chinese remedy for headache, fever and gastrointestinal problems. Clinical trials have shown that the compound reduces the unpleasant effects of chemotherapy. Trials will soon begin to evaluate whether it also enhances the action of the chemotherapy. The researchers’ main accomplishment, however, is the development of a platform technology that combines quality control, a robust database, clinical trials and herbal resources to produce plant-based medicines with a biologically consistent result.

“We’re in a new frontier,” said Yung-Chi “Tommy” Cheng, Ph.D., the Henry Bronson Professor of Pharmacology, who is leading efforts at Yale to advance the study of traditional Chinese medicine.

Prehistoric origins of herbal medicine

Most users of herbal remedies point to anecdotal rather than clinical evidence of efficacy—but that evidence, like the botanicals themselves, has firm roots in many countries around the world.

Otzi the Iceman, the 5,300-year-old mummified human discovered in the Italian Alps in 1991, carried his own medicine kit, which contained birch fungus, a natural antibiotic. An autopsy showed that Otzi suffered from intestinal parasites, so the birch may have come in handy to fight the infestation. Birch fungus also could have served as a styptic pencil to close minor cuts.

In the Middle Ages, ergot, a fungus that grows on rye and other food grains, caused ergot poisoning in people who ate bread made from rye, barley or wheat infested with the parasite. Characterized by constriction of blood vessels, ergotism often led to gangrene. It was also marked by convulsions and hallucinations known as Saint Anthony’s fire. (The alkaloids in ergot were a key ingredient in the experiments performed by a Swiss chemist that led to the synthesis of LSD.) Ergot was also used in 16th-century Europe to stop postpartum bleeding and to induce abortions; its first recorded use as an oxytocic was 1582.

And also in the 16th century, Western explorers like Sir Walter Raleigh were impressed by the way in which South Americans killed prey—and sometimes Europeans—with arrows poisoned with curare. Curare, which is concocted from several plants, kills by isolating muscle tissue from contact with nerves, eventually paralyzing the victim’s respiratory muscles. The powers of curare weren’t tamed until 1942, when two physicians converted it into a muscle relaxant that allowed lifesaving procedures to be performed more rapidly and effectively.

The coca leaf has been a chief target in the war on drugs, but it was woven into the fabric of Andean society thousands of years before its illicit use as the raw material of cocaine. To this day, indigenous people in South America chew on the leaf as a stimulant and appetite suppressant, helping them get through a day of hard labor on the mountainsides. Brewed as a tea, coca combats altitude sickness and settles the stomach.

Since the Enlightenment, the healing ability of botanicals has been rooted in hard science: the British physician William Withering, M.D., noted in a seminal 1785 paper that the garden herb foxglove, also known as digitalis, alleviated a deadly accumulation of fluid in the lungs and other body tissues—a condition then called dropsy—in patients with congestive heart failure.

Humankind has also been wary of medicinal plants. They tend to trigger a bitter taste on the tongue, long recognized as a poison detector. They also vary in their potential to harm as well as heal. As Withering himself acknowledged, the perils of foxglove were well-known.

Foxglove has long since been converted into a standardized drug known as digoxin, but controversy over its use—including its potential toxicity—continues to this day. But the disputes are based on numerous studies, something that can’t be said about many other botanicals with supposed healing properties. The longstanding use of herbal preparations notwithstanding, they have a hard time getting a seat at the table dominated by Western pharmaceuticals, which rely heavily on the clinical trial, largely unheard-of until the 1920s.

Star anise is a staple in Chinese spice cabinets, in part because of its licorice-like flavor and in part because it helps promote healthy digestion. Teas made from it have traditionally been used to treat colicky babies. However, in 2003 the Food and Drug Administration (FDA) issued an advisory to warn consumers against drinking the tea—Chinese star anise was sometimes adulterated with Japanese star anise, a toxic species of the herb. It also provides the key ingredient for the anti-flu drug oseltamivir phosphate, marketed under the name Tamiflu by Roche. When reports of avian flu hit Asia in 2005,
Chinese officials reported a run on star anise, both by people who wanted its protective properties and by those who wanted it to flavor their food. Eating the spice offers no protection against flu, however, because the active ingredient, shikimic acid, is obtained only after a laborious extraction process.

For over two millennia herbal treatments have been a mainstay of Chinese medicine, whose techniques also include acupuncture and massage. Among the herbs used are yarrow, to treat the common cold, colic, indigestion and toothache; aloe, which has a laxative effect and is also used to treat wounds and burns; cardamom seeds for infections of the digestive tract as well as nausea and vomiting; and devil’s root, for chronic bronchitis. Traditional Chinese medicines are made of a blend of herbs, usually a principal ingredient and three others intended to reinforce the effects of the principal herb, mitigate its side effects or treat a coexisting disease pattern.

Finding a consistent dosage

Complementary and mainstream medicine “have a different type of approach” to healing, but “eventually, they’re going to meet,” said Cheng. “Chinese medicine has been used for years and is still used today.” He knows full well that “mainstream medicine has always been suspicious” of such methods of healing, even if their popularity has risen in Western countries. By 1997, according to the NCCAM, spending on complementary and alternative medicines totaled between $36 and $47 billion in the United States alone. By comparison, the major pharmaceutical companies registered $251.8 billion in sales in 2005, according to the most recent figures from IMS Health, a consulting firm that tracks the drug industry.

In 1999 Yale’s Office of Cooperative Research worked with Cheng to found PhytoCeutica, a company devoted to making cancer drugs out of herbs used in traditional Chinese medicine. That this project is connected with a leading research institution at all reflects a major shift in attitude, said James C. Whorton, Ph.D., professor of medical history and ethics at the University of Washington School of Medicine in Seattle and the author of Nature Cures: The History of Alternative Medicine in America. “It would not have happened 25 or 30 years ago,” he said. “A faculty member wouldn’t risk having his name associated with some group that was doing alternative medicine. It was career suicide.”

Cheng also hopes to advance the acceptance of traditional medicines at the international level. In December 2004 he founded the Consortium for the Globalization of Chinese Medicine, which counts as members 61 institutions around the world, including seven from industry. Member institutions include the School of Medicine; the Department of Intramural Research Affairs at the National Health Research Institutes of the NIH; and academic and research institutes in Canada, China, Great Britain, Hong Kong, Singapore, Taiwan and the United States. The consortium’s goals are to develop platform technologies for producing Chinese medicines, to facilitate collaboration among institutions and to develop medicines based on Chinese herbal preparations as well as traditional medicines from other countries. “The spirit is to share the technology,” said Cheng, who chairs the consortium. “This is something no company or institution can do by itself.”

The key to success for producing Chinese herbal remedies, aside from showing that they work, is getting a consistent formula to deliver the drug. This concern for consistency is what separates PhytoCeutica from other purveyors of Chinese herbs. The alternative treatment landscape is littered with botanical products that looked like promising cancer therapies but ultimately failed or were deemed dangerous. When such products are taken in their herbal form or as unregulated supplements, however, the bath water comes with the baby. “With two different preparations, you come up with a different result,” Cheng said. “The chemical composition is going to be different.”

For example, PC-SPES, a widely touted herbal concoction for prostate cancer, was removed from the market after reports that it caused cardiovascular and other problems. “Different formulations were found to have different impurities,” said Edward Chu, M.D., deputy director of the Yale Cancer Center. If the impurities had been removed, it might have worked, he said.

For the past few years PhytoCeutica has been conducting early-stage clinical trials of a traditional Chinese medicine formula that goes by the designation PHY906 and acts as an adjuvant to chemotherapy for cancer. For competitive reasons, the company, which has a patent for PHY906 in the United States and other countries to treat cancer, won’t release many details about the herbs used in the compound. Cheng said it is a traditional Chinese medicine derived from four different plants whose therapeutic ingredients work better together than each does alone. Unlike other plant-based drugs with a single active molecule, however, PHY906 is multipronged. “Chinese medicine always claims to have multiple chemicals hitting multiple targets,” explained Cheng, referring to the traditional practice of blending several herbs to produce a single remedy. “There is a possibility this could be a shortcut to look for medicines which have a broad spectrum of usage, and also cover most patients.”

The herbs used to make PHY906 are typically brewed as a tea or put in a blender, according to Chu, who was born in the United States, but whose great-grandfather practiced Chinese herbal medicine. The plants have been used historically to treat headache, fever, swelling and a host of gastrointestinal problems.

Initial Phase I trials involving 17 patients found that PHY906, used in combination with a standard two-drug regimen for colon cancer, caused no adverse effects and appeared to reduce the toxicity of the chemotherapy. The next step of the trial, with 29 patients, is to determine whether PHY906 will enhance the action of the chemotherapy and shrink tumors as it did in animal models, Cheng said. Another trial tested the compound with capecitabine, marketed by Roche under the name Xeloda to treat liver cancer, and again found no adverse effects from PHY906. Data are still being gathered to assess the effects of the traditional formula on quality of life, but initial findings, said Cheng and Chu, are encouraging.

“It seemed like the anti-tumor activity of Xeloda was improved upon the addition of the herb,” said Chu. “In Phase I, patients seemed to tolerate the combination pretty well, and there are some patients who are continuing to receive treatment for a lot longer than with chemotherapy alone.” In Phase II of that trial, the investigators will see “whether it can cause the tumors to shrink and allow the patients to be living with their cancer for a longer period of time,” Chu said. In addition, a new trial at Yale-New Haven Hospital is testing PHY906 in combination with Xeloda for treatment of pancreatic cancer.

Chu and Cheng still don’t know how PHY906 works, but they suspect that it inhibits certain proteins or clears a path to allow cancer drugs to get into cells. “To be honest, as a patient you don’t really care how the compound works,” Cheng said. That people have used these herbs for nearly two millennia, and still do in the age of pharmaceutical plenty, makes for a tough-to-ignore case. “A number of our friends who have had cancer and who have taken these herbs have benefited,” Chu said. The point of the research, however, is to “take it out of the mystique and prove in fact that there is real clinical efficacy.”

If proven effective, PHY906 could become the first botanical prescription medicine developed from multiple herbs to be approved for oral administration by the FDA, said Cheng. (The FDA recently approved an unrelated topical application based on herbal medicine for treatment of genital warts, Cheng said.)

While the trial results have looked good so far, this botanical-to-pharmaceutical therapy still faces an uphill battle. “So far, I have not seen any herb go beyond Phase III,” said Lixing Lao, M.D., Ph.D., director of traditional Chinese medicine research at the University of Maryland School of Medicine. Another concern endemic to herbal medicines—and one that has ended trials in the past—is getting a consistently successful formula. “We have standards of chemical identities,” said Peter Goldman, M.D., professor emeritus of pharmacology at Harvard, who has called for stronger research on medicinal herbs. “How sure are you that what you have from a chemical perspective could actually be reproduced?” he asked. Lao added that the potency of an herb can vary greatly from sample to sample. “Different fields in different seasons may come up with different chemical compositions.”

PhytoCeutica’s work on PHY906 stems from a collaboration with SunTen Phytotech, a Taiwanese herbal medicine company that had manufactured the compound in pill form for years. What’s new is the application of PhytoCeutica’s platform technology, called Phytomics, and quality control methods to develop a standard consistency for the compound. Cheng said PhytoCeutica uses modern bioinformatics, “including chemical and biological fingerprints,” to obtain the same formula each time. “We compared our product with the company’s product that was made previously, not following current good manufacturing practices,” Cheng said. “As far as chemistry and biology are concerned, they are different. The manufacturing practices are a critical element to ensure the product’s consistency.”

The success of PHY906, according to Nature Cures author Whorton, depends on whether “they’ve actually identified the compounds present in the crude herbs and isolated that in pure form, the way you’d isolate morphine from opium.” If that works, then PhytoCeutica and its Taiwanese partner can separate from the large pack of herbal medicine companies. Paul Talalay, M.D. ’48, professor of neurology and pharmacology at Johns Hopkins School of Medicine, said that will be necessary because many products make bogus claims, are dangerous or both. A 1994 federal law allows sellers of alternative remedies to make health claims without adhering to the same strict standards as a pharmaceutical drug. The law, the Dietary Supplement Health and Education Act (DSHEA), essentially deregulated the industry—the FDA can’t remove a product until there is overwhelming evidence that it causes harm—and spurred more intense interest in readily available products. DSHEA was “a disaster” that “confuses our ability to handle disease properly,” Talalay said. Everything should undergo the same standards of testing, he said.

The program as developed by Yale may be an excellent model for raising standards, according to Jeanne A. Drisko, M.D., who developed an integrative-medicine program at the University of Kansas and served on an Institute of Medicine committee that wrote a report on alternative medicine. “The only way that we’re going to separate those [remedies] that work from those that don’t is to do the research,” she said. “And it has to be done in a partnership between the conventional practitioner and the complementary and alternative practitioner.” YM