The alternative pharmacological and biological treatments discussed in this chapter are an assortment of drugs and vaccines that have not yet been accepted by mainstream medicine. If and when they are accepted, many of these drugs and vaccines will fit into conventional medicine as it is practiced today. Thus, these treatments differ from other alternative health measures in this report because, by and large, they do not represent an entirely new theory or unified approach to health and disease.

Despite their diversity, the alternative pharmacological approaches share some or all of the following themes:

• Unlike many mainstream drugs, most unconventional substances are believed to be nontoxic.

• Many are directed not toward eradicating a specific disease entity but toward stimulating the patient's immune system to fight the onslaught of a pathological condition or organism. Frequently, these methods may have to be tailored to individual patients to be effective.

• For other approaches, practitioners may postulate an entirely new defense system altogether. Other alternative substances are derived from old Native American herbal remedies or are turn-of-the-century remedies that were cast aside during the rapid advance of biomedicine.

Hundreds of alternative drugs and vaccines could have been included in this report. The ones that are included were chosen because they met one or more of the following criteria:

Therapeutic promise. Available evidence suggests that they may be effective.

• Wide use. Because they are now used by many people, public health considerations indicate that they should be investigated. If any of these products prove harmful, that news needs to be spread quickly; if any prove effective, this should be officially recognized and they should be put to further use. An up-todate example is the use of cartilage products

for acquired immune deficiency syndrome (AIDS), cancer, and arthritis. Since a "60 Minutes" television program about them in late February 1993, some 50,000 Americans are currently reported to be taking shark cartilage even though properly designed trials have not yet been conducted. (Another consideration besides safety and effectiveness for the users is that demand for these products entails destroying many sharks.) Ozone is another example of a substance now being used widely-particularly as a self-medication in the AIDS community-without solid evidence of its usefulness.

Subject of controversy. Some other pharmacological or biological products have been the subject of long-standing controversies that need to be resolved. This point is particularly true for certain medicines derived from Native American remedies, such as the Hoxsey method and Essiac.

Former use or use elsewhere. Some products have been tested and well documented in the scientific literature but for various reasons have fallen by the wayside. An example is Coley's toxins, an immunotherapy for cancer that was developed at the turn of the century by a New York bone surgeon and which is currently being used in China and Germany. Similarly MTH-68, a nontoxic, biological vaccine, is reported to buttress the immune system against cancer. Another example is the use of a local anesthetic (often, novocaine) for neural therapy to combat chronic pain, allergies, and other problems; this approach is in wide use in Europe.

A major impediment to full investigation of alternative pharmacological treatments is the high expense of conducting the trials necessary to meet Food and Drug Administration (FDA) approval. Nearly every one of the few drugs that FDA approves each year is marketed by one of the major pharmaceutical companies. Nevertheless, even well-capitalized biotechnology firms have sometimes been driven out of the marketplace by the difficulty in meeting FDA requirements.

Another problem for many alternative materials such as herbs, nutrients, and common chemicals-is their lack of sponsorship. Because they are in the public domain and therefore inexpensive and not patentable, drug companies under

standably lack interest in investing the enormous sums required for full trials. Therefore, most such alternatives lack both sponsors and funding for clinical trials of their safety and effectiveness.

Marketing most of the substances discussed in this chapter is not allowed by FDA on the basis of its interpretation of Title 21, article 355, of the U.S. Code, which states that unless a developer has presented "substantial evidence" of a drug's safety and efficacy, the FDA can deny approval for marketing that substance. "Substantial evidence" is defined as "adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved."

Many alternative medical practitioners have attempted to market new drugs or vaccines under this statute, but few have succeeded. The failure often occurs because "qualified experts" are defined as those who adhere to mainstream medical practices. To be an alternative practitioner has, until now, been reason enough to disqualify a person to evaluate the usefulness of the drug in question.

Moreover, "clinical investigations" are generally interpreted to mean randomized, doubleblind, placebo-controlled studies (see the "Research Methodologies" chapter) of the kind that only pharmaceutical companies and major medical centers can afford to conduct. This is true despite a declaration by Jay Moskowitz, former deputy director of the National Institutes of Health in September 1992, that "not all alternative medical practices are amenable to traditional scientific evaluation, and some may require development of new methods to evaluate their efficacy and safety." Thus, the reluctance of conventional medicine to accept for examination and possible use the materials assessed here appears to be tied to measuring them with the wrong yardstick.

The remaining sections of this chapter deal with the existing research base for 14 specific treatments, future research opportunities for these 14 treatments, and key issues and recommendations that are relevant to all such biological and pharmacological treatments. Each treatment fits one or more of the criteria cited earlier-such as wide use, controversy, and therapeutic promise-and may require selection

or development of appropriate methodologies for proper evaluation.

Research Base for Specific Treatments

Hundreds of potentially useful alternative drugs or vaccines are supported by data indicating that they may be useful in the treatment of such diseases as cancer, AIDS, heart disease, hepatitis, and other major health problems. What follows is only a sampling of the many products available for study.

Antineoplastons

Antineoplastons are peptide fractions originally derived from normal human blood and urine, although a method for synthesizing them was subsequently developed by Dr. Stanislaw Burzynski. Burzynski has named some of these peptides A2, A5, A10, and AS2-1. He first discovered antineoplastons as a graduate student in Poland in 1967 (Moss, 1989) when he compared normal urine and urine from people with cancer and noted an anomalous streak on electrophoresis of the normal urine that was not present in the urine of cancer patients. He then chemically defined these antineoplastons at Baylor College of Medicine in Houston (Burzynski, 1973, 1976, 1986; Burzkynski and Kubove, 1986a, 1986b; Moss, 1992). He depicts these substances as a newly discovered, natural form of anticancer protection, apart from the lymphocyte system.

Burzynski reported that the antineoplaston peptides are essentially nontoxic (Burzynski, 1986) and that preliminary clinical results indicated tumor responses (shrinkages) in a number of difficult cases, most of which involved subjects who had exhausted conventional treatments (Burzynski, 1986; Moss, 1992). He also reported at the 1992 International Conference on AIDS that some patients infected with human immunodeficiency virus (HIV) responded to antineoplastons by a marked increase in certain white blood cells (CD4+ lymphocytes); other observations included increases of energy and weight and a decrease of opportunistic infections.

Although antineoplastons have been employed against a wide variety of tumors, the greatest interest has been generated by using them with otherwise incurable brain cancers. Burzynski reports that he has been most successful treating

prostate cancer and brain cancer (specifically, several forms of childhood glioma) and has had good results with (in descending order) nonHodgkins lymphomas and pancreatic cancers, breast cancer, lung cancer, and colon cancer. Burzynski has published scores of medical articles in peer-reviewed journals, mostly in Europe (Bertelli, 1990; Bertelli and Mathe, 1985, 1987; Kuemmerle, 1988). At the 18th International Congress of Chemotherapy in Stockholm on July 1, 1993, more than a dozen papers were presented by researchers from Brazil, Holland, Japan, Poland, and the United States in a special session on antineoplastons.

In the late 1970s, controversy began swirling around Burzynski when he left a position at Baylor College of Medicine during a disagreement about an interdepartmental transfer, research freedom, research funding, and maintenance of a private medical practice. Since then, Burzynski has worked independently, paying for his research from patients' fees. Some research physicians are fascinated by his work, but many others have attacked it. On one hand, after conducting a review of a "best case series" (see app. F), including a site visit in October 1991, the National Cancer Institute (NCI) concluded that antitumor activity by antineoplastons may have been demonstrated by Burzynski in seven cases of incurable brain cancer (confirmation by NCI communication, 1994). Consequently, NCI agreed that conducting confirmatory trials would be a worthwhile effort. On the other hand, Saul Green, formerly a researcher at Memorial SloanKettering Cancer Research Center, attacked treatments with antineoplastons in the Journal of the American Medical Association (Green, 1992).

The trials that NCI proposed are Phase II studies (that is, small-scale clinical trials), in which researchers examine the effectiveness of a potential treatment in some 25 to 40 subjects. The Office of Alternative Medicine (OAM) has contributed to the funding of these trials; Burzynski has participated in the planning steps and provided a supply of synthetic antineoplastons A10 and AS2-1. (He informed NCI that he no longer uses urine-derived products.) In late 1993 and early 1994, three sites opened enrollment for these trials: Memorial Sloan-Kettering in New York, the Mayo Clinic in Minnesota, and the Clinical Pharmacology Branch of NCI in Maryland. The subjects to receive antineoplastons are patients with

two types of brain tumors, gliomas and astrocytomas. They are required to have a particularly small tumor, at Burzynski's request.

Because of the possible promise of some of Burzynski's products and the controversy surrounding them, further research should be conducted.

Cartilage Products

Investigations of cartilage to improve health began with a graduate student wondering whether cartilage could assist wound healing. Physicianresearcher John Prudden decided to find out, using a powdered and washed cartilage product. There is now a long list of reported effects of cartilage preparations, including accelerating wound healing, possessing topical anti-inflammatory capability, alleviating autoimmune diseases, relieving osteoarthritic pain, alleviating scleroderma (a disease in which the skin hardens), easing skin symptoms of herpesvirus infections, alleviating psoriasis (a chronic, scaly skin disease), and inhibiting a wide spectrum of cancers (Prudden, 1985). A recent report adds relieving swollen and tender joints of patients with rheumatoid arthritis (Trentham et al., 1993). This study bolsters previous anecdotal reports that cartilage products can palliate the painful effects of rheumatoid arthritis.

The various cartilage products under study or reported on anecdotally derive from cattle, sheep, sharks, and chicken cartilage; some products, such as Prudden's "Catrix," are a form of repeatedly powdered and cleaned cartilage; others are relatively pure substances, such as the type II collagen used by Trentham et al. (1993) in a randomized double-blind trial. (See app. F for types of trials.)

The popularity of cartilage products increased dramatically after the television program "60 Minutes" produced a segment on the possible benefits of shark cartilage in late February 1993, citing a 16-week clinical trial in Cuba with some allegedly positive results. Medical centers have since been inundated with calls about the effectiveness of shark cartilage in treating AIDS, cancer, and arthritis. Since the show, this product has been aggressively marketed in the United States, and some 50,000 Americans are said to be currently taking shark cartilage at an individual cost of approximately $7,000 or more per year.

The numbers of persons and amount of money they are spending are together sufficient reason to undertake an evaluation of the safety and effectiveness of shark cartilage treatments.

As for one or more scientific bases, a scientific hypothesis for the effectiveness of cartilage products as anticancer agents relates to their effects on blood vessel formation. A substance present in very small amounts in cartilage is believed to act by inhibiting angiogenesis, or interfering with the ability of a tumor to create a network of new blood vessels. It has been shown that if a tumor cannot establish a new blood network, it cannot grow any larger than the point of a pencil (Brem and Folkman, 1975; Folkman, 1976; Langer et al., 1976). Thus it has been proposed that cartilage, and appropriate substances purified from cartilage, may act against cancer through angiogenesis-inhibiting effects.

A researcher at NCI has proposed another anticancer mechanism involving a class of proteins that are produced in normal tissues such as cartilage and bone (Liotta, 1992). These proteins are called tissue inhibitors of metalloproteinases (TIMPs); TIMPS appear to block the action of certain metalcontaining enzymes (the metalloproteinases) that help tumor cells to invade surrounding tissue.

A detailed explanation for the successful treatment of rheumatoid arthritis with type II collagen (Trentham et al., 1993) is still being sought. A working hypothesis is that the large amount of collagen taken by mouth (in daily doses in orange juice) suppresses autoimmune reactions; this observation was made in previous studies with animal models of autoimmune diseases and in small pilot human studies of patients with multiple sclerosis and with rheumatoid arthritis. Possibly the collagen stimulates certain immune system cells to produce anti-inflammatory cytokines.

In reviewing the scientific literature on cartilage, Prudden (1985) described other healthpromoting activities studied by other researchers. Wound-healing activity is attributed to a polymer of N-acetyl glucosamine. Inhibition of cell division and inflammation appear to be attributable to a different "fraction" of cartilage. Although practitioners of alternative medicine tend to prefer dealing with natural substances, such as cartilage, the more conventional academic view is that such mixtures must be separated into identifiable, pure products.

The most recent work with cartilage itself, rather than purified products, is probably the anticancer shark cartilage studies. NCI informally reviewed the results of the 16-week Cuban study that "60 Minutes" cited when the chief Cuban investigator presented a seminar in the United States. Staffers from NCI's Cancer Treatment Effectiveness Program noted the uncertainty of accurate drug delivery by enemas (apparently enemas had to be used because the preparation's taste was so bad that subjects would not eat it) and what they called the lack of any clear benefits in the cases described. Nevertheless, the NCI staff indicated that it would be willing to reconsider this product if additional data should prove positive.

Charles Simone-an oncologist from Lawrenceville, NJ, who has NCI research experience examined the results of the Cuban study for "60 Minutes" and was guardedly optimistic. In his own practice, he has treated some patients who initiated self-medication with cartilage. He has said that some of his patients experienced dramatic improvement, including the clearing of liver metastases and rapid reduction in certain prostate antigens in prostate cancer (Simone, 1993). Simone provided OAM with a copy of a protocol (study plan) and has begun a prospective study (see the glossary and app. F) on shark cartilage. In early 1994, he received IND (investigational new drug) approval from FDA for shark cartilage.

Most previous studies with cartilage have used bovine cartilage. Catrix, a trade-named product derived from the tracheal rings of cattle, was developed by John Prudden, who holds a patent on the use of all cartilage products (including shark) and an FDA IND permit to conduct research studies. Prudden was formerly a surgeon at Columbia-Presbyterian Hospital in New York and associate professor of clinical surgery at Columbia University. He has published more than 60 papers on the use of cartilage, mostly to accelerate wound healing but also to treat psoriasis, cancer, and rheumatoid arthritis. In 1985, Prudden reported on results of a study in which 31 cancer patients were treated continually with

Catrix. The overall response rate, measured as a greater than 50-percent reduction in tumor size, was reported as an unusually high 90 percent; 61 percent had complete disappearance of tumors.1 Both oral and injectable forms of Catrix were used, and Prudden concluded that the oral route was superior.

Clinical trials using Catrix in kidney (renal cell) cancer patients are currently under way at Westchester Medical Center in Valhalla, NY, and Royal Victoria Hospital in Montreal. Renal cell cancer is an intractable tumor, resistant to cure, relief, and control; response rates with Catrix are said to be about 25 percent (Prudden, 1993).

The proposed usefulness of cartilage for AIDS patients would be for treatment of AIDS-related cancers such as Kaposi's sarcoma and AIDSrelated lymphoma and for opportunistic infections caused by viruses other than HIV. Although cartilage is reported to have activity against herpes infections, it does not directly affect herpesviruses (Prudden, 1993). Prudden proposes that the antiviral effects result from stimulation of patients' immune systems; this point should be explored in more detail.

EDTA Chelation Therapy

Chelation is the major form of alternative therapy for cardiovascular disease and one of the most popular alternative pharmacological treatments. Chelation employs ethylene diamine tetraacetic acid (EDTA), a material that readily binds to metallic ions. EDTA is used in standard medicine as the preferred treatment for lead poisoning as well as for removing more than a dozen other toxic metals ranging from cadmium to zinc (Berkow, 1992).

Since shortly after EDTA was synthesized in the 1950s, its use has been suggested to treat heart disease and circulatory problems, including atherosclerosis (Clarke et al., 1955), high blood pressure (Schroeder and Perry, 1955), angina pectoris (Clarke et al., 1956), occlusive vascular disease (Clarke, 1960), and porphyria (Peters, 1960). Chelation has also been suggested as a potential treatment for rheumatoid arthritis