NIH Complementary/Traditional

Research Base For Specific Treatments
Key Issues and Specific Recommendations

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~ 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 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) non-Hodgkins 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 Sloan-Kettering 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. Physician-researcher 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 metal-containing 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 health-promoting 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 AIDS-related 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 (Boyle et al., 1963) and even as a preventive for cancer (Blumer and Cranton, 1989).

Several mechanisms have been proposed for the therapeutic action of EDTA. Since the molecule is known to be able to incorporate a metal ion into its own ring structure, it may maintain cellular health by removing those ions that cause harmful peroxidation of lipids (fatty materials). EDTA is also believed to remove calcium particles deposited in the arterial wall--various kinds of plaques--by analogy to its standard use in heavy-metal poisoning. But it may also lower the ionized calcium levels by blocking the slow calcium currents in the ~arterial wall, thus functioning as a kind of "calcium-blocking agent," a category of drugs known to have potent coronary vasodilating effects (Casdorph, 1981). EDTA has also been identified as acting to increase the concentration of a vasodilator (Cranton and Frackelton, 1989).

Most recently, the various mechanisms proposed for EDTA's therapeutic action have been brought together under a unified but controversial theory that they all involve protective effects against detrimental actions of free radicals (Cranton and Frackelton, 1989). This protection may lead indirectly to such activities as removing deposits from the walls of arteries or dilating blocked arteries.

Various peer-reviewed articles support the use of EDTA chelation in heart disease because of the observed effects on the health of patients, but clear demonstration of physiological change has been possible only in the past few years. In the early 1980s, the problem was how to directly measure arterial effects of EDTA, because measurements of the size (diameter) of arteries were accurate within only 25 percent (Cranton and Frackelton, 1982); ~yet dilations of 10 to 15 percent may have significant (doubling) effects on blood flow (Cranton, 1985; Olszewer and Carter, 1989). One 1982 study did report decreased blockage of arteries in 88 percent of 57 patients by means of a noninvasive analysis (McDonagh et al., 1982) that relies on a technique developed by Langham and To'mey (1978). Later research involving some of the same investigators (Rudolph et al., 1991) using ultrasound showed a decrease in blockage of carotid arteries using chelation therapy that was statistically significant in both males and females and was an average of 21 percent lower than initial values. The investigators calculated large improvements in blood flow as a result of the decreased blockage.

Furthermore, a large retrospective study of 2,870 patients in Brazil showed that 89 percent of the patients treated with EDTA had marked or good improvement (Olszewer and Carter, 1989). Olszewer et al. (1990) followed the retrospective study with a small, randomized, double-blind clinical trial of EDTA treatments for 10 men with peripheral vascular disease. After 10 of 20 intended EDTA treatments, it was clear that some patients were showing dramatic improvements. When the code that identified which patients were receiving ~medication was broken, the group that had improved were all identified as persons who received EDTA. All patients were then placed on EDTA treatment, and the ones previously receiving placebo showed improvement comparable to that of the first EDTA group. The group continuing on EDTA showed additional improvements as well, although later progress was not as dramatic as the initial changes.

Chelation is currently available in nearly every State of the United States as well as many foreign countries. In the United States, the four major organizations promoting acceptance of chelation therapy are the American Board of Chelation Therapy, the American College for Advancement in Medicine, the Great Lakes Association of Clinical Medicine, and the International Bioxidative Medicine Association. Chelation therapy is administered as an outpatient treatment, costing $75 to $120 per visit; the average cost for a course of 20 to 30 treatments is approximately $3,000. Since 1960, 500,000 patients have received chelation in more than 5 million treatments.

The toxicity of EDTA is a matter of some dispute. Advocates claim that it is essentially ~nontoxic, with approximately the same "danger" as that of normal doses of aspirin. They explain that early adverse effects, especially on the kidney, resulted from preexisting kidney disease or from using greater doses and rates of administration than those now recommended (the protocol available from the American College of Advancement in Medicine for use of intravenous EDTA also includes dietary supplements with multivitamins and trace elements). Although some reports claimed EDTA-related deaths, proponents state that these claims were erroneous, explaining, for example, that some deaths resulted from heavy-metal toxicity. See Cranton and Frackelton (1989) for references reviewing the field.

Hundreds of physicians are convinced that EDTA chelation therapy is of greater benefit to their patients than conventional treatments that are more dangerous and costly, such as bypass operations or toxic cardiotonic drugs such as digoxin. For example, Cranton (1985) compared 4,000 deaths from bypass surgery over a 30-year period with fewer than 20 associated with EDTA treatment (both procedures had approximately 300,000 patients during that time). Proponents also note that in issuing an IND permit to the American College of Advancement in Medicine to study EDTA to treat peripheral vascular disease, ~FDA officials indicated that "safety is not an issue" (Olszewer and Carter, 1989).

A double-blind, placebo-controlled study that might have settled the question of the usefulness of EDTA treatment was begun at three military hospitals in the 1980s under the FDA-approved IND application cited in the preceding paragraph. This study was dropped in November 1991, reportedly because of the exigencies of Operation Desert Storm in the Persian Gulf. At that time, 31 patients had completed their dosages, but the double-blind code was not broken.

At present, it is estimated that the study could be resumed by an interested sponsor at a cost of $3.75 million for the remaining 150 patients, or $25,000 per patient. Since EDTA is an unpatented drug in the public domain, no drug company is likely to sponsor this research or develop it for sale. Proponents of alternative medicine believe that EDTA could and should be evaluated in less costly ways. (See the "Future Research Opportunities" section.)

Ozone~Anecdotal claims abound for ozone therapy among persons infected with HIV (the virus causing AIDS). Yet there have been only a few test tube (in vitro) and clinical evaluations of ozone as an antiviral therapy.

One such study (Wells et al., 1991) showed that ozone caused test tube inactivation of HIV by inhibiting an enzyme called reverse transcriptase and by disrupting viral particles and viral attachment to target cells. Ozone in nontoxic concentrations (4.0 mg/mL) was also shown to inactivate this virus in both serum (Freeburg and Carpendale, 1988) and whole blood (Wagner et al., 1988). These test tube results appeared promising, but that was true for a number of other proposed AIDS treatments that were not subsequently successful for treating human beings.

More recently, two small sets of clinical trials using ozone-treated blood have been described in published reports (Garber et al., 1991; Hooker and Gazzard, 1992) and one clinical study using rectal administration of ozone (Carpendale et al., 1993). Garber and colleagues reported on withdrawing blood from patients infected with HIV, treating the ~blood with ozone, and returning the blood to the patient. Their hypothesis was that this technique would return killed HIV to patients that could then stimulate their immune systems.2 In a Phase I study, which examines safety of the treatment in a small number of subjects, ozone therapy was reported to be safe and also possibly effective; the latter was suggested because 3 of 10 patients showed some improvement in various measurements associated with HIV infection. (Study participants were HIV-infected persons who either refused or could not tolerate zidovudine [AZT] treatments.) Next, a Phase II randomized, double-blind study was initiated to look for signs of effective treatment in 14 subjects. On the basis of this 12-week study and blood, biochemical, and clinical laboratory tests, the authors reported that ozone had no significant effect.

Although a suggestion has been made that different dosing or other procedural variations might have produced positive results, the work of Hooker and Gazzard corroborates the negative results discussed above. Hooker and Gazzard conducted an open study of nine patients, using a procedure like that of Garber and colleagues and following the participants for 12 weeks. These researchers concluded, "We agree with Garber et al. that there is no ~evidence to support a belief that ozone, used by this method, is beneficial during HIV infection."

Nevertheless, persons applying or receiving ozone therapy tend to rely on the test tube results concerning ozone killing HIV and stimulating interferon, and on anecdotal information such as the following: To obtain additional information on ozone therapy in actual practice, the Research Department of Bastyr College of Natural Health Sciences in Seattle collected anecdotal data in 1993 from three physicians who used ozone in the treatment of their HIV and AIDS patients. In examining the case records of nine cases of HIV-positive patients treated with ozone by a physician in Washington State, Bastyr scientists concluded that some patients with CD4 counts above 500 showed increased counts of these cells after several weeks of treatment.3 Patients with CD4 counts of 200 and below (more critical levels) did not seem to respond, although the doctor reported anecdot-ally that these patients were doing well clinically. Bastyr's researchers expressed interest in conducting a clinical trial.

~A physician with a 5-year history of interest in ozone therapy, John Pittman, recently announced plans to open the North Carolina Bio-Oxidative Health Center in August 1994 and provide there a holistic treatment approach that includes ozone therapy. Previously, Pittman had closed his office to comply with an order from the State board of medical examiners, which considered ozone use nonconventional. North Carolina subsequently passed a "freedom of medicine law" that allows physicans choice among therapies so long as they have not been proved ineffective or dangerous. Pittman has indicated that the center will collect data on the effectiveness of its treatments.

A different approach to ozone use by AIDS patients appears to deserve further exploration. This application is not for attacking HIV, but for treating a debilitating and deleterious symptom--diarrhea. Carpendale et al. (1993) treated five patients with AIDS-related, intractable diarrhea using rectal administration of ozone gas daily for 3 to 4 weeks. This choice of treatment was based on reports from the 1930s that ozone was effective for three kinds of diarrhea. Diarrhea in three of the five patients was resolved, and one other patient improved as well. The ozone had no toxic effects. The authors suggest that further ~investigation is warranted, that longer treatment periods and different doses be studied, and that attention be paid to whether good results depend on the initial immunological state of the patients.

The fact that many people are receiving some kind of ozone treatment and that some practitioners continue to regularly apply such treatments is sufficient reason to recommend that definitive studies be undertaken to determine whether these treatments have any utility. Possibly, Pittman's new center will be able to provide this information.

Immunoaugmentative Therapy

Immunoaugmentative therapy, which was developed by Lawrence Burton, is "one of the most widely used unconventional cancer treatments," according to the Office of Technology Assessment (OTA)(Office of Technology Assessment, 1990). It has also been one of the most bitterly contested. The process is patented, and some details of it appear to have been kept secret, although this situation may change since Burton's death in early 1993. The ~attempt to achieve a fair evaluation of immunoaugmentative therapy led some of its proponents, such as Frank Wiewel of People Against Cancer, to work for the establishment of OAM (Mason, 1992).

Essentially, immunoaugmentative therapy is an experimental form of cancer immunotherapy consisting of daily injections of processed blood products. Several blood fractions recovered by means of centrifugation are used in an attempt to restore normal immune function to the person with cancer. These fractions are said to include the following substances: (1) deblocking protein--an alpha-2 macroglobulin derived from the pooled blood serum of health donors; (2) tumor antibody 1 (TA1)--a combination of alpha-2 macroglobulin with other immune proteins (IgG and IgA) derived from the pooled blood serum of healthy donors; and (3) tumor antibody 2 (TA2)--also derived from healthy blood serum but differing in potency (and possibly in composition) from TA1.

Proponents of immunoaugmentative therapy hypothesize that the tumor antibodies attack the tumors and that the deblocking proteins remove a "blocking factor" that prevents the ~patient's immune system from detecting the cancer.

Originally a New Yorker with a clinic in Great Neck, Long Island, Burton established a new base in Freeport, the Bahamas, in the late 1970s after he failed to obtain FDA approval for his blood fraction medications. This move followed nearly 20 years of work with tumor-inducing and tumor-inhibiting factors at various institutions. During the 1960s and 1970s, Burton and a colleague, Frank Friedman, reported discovering cancer-inhibiting factors in mice (Friedman et al., 1962). In one experiment, daily administration of these factors was said to eliminate palpable disease in 26 of 50 mice with leukemia. The treated animals appeared to survive significantly longer than the controls. In another experiment, Burton reported that 37 of 68 experimental animals survived for an average of 131 days without any evidence of leukemia, versus a 12-day average survival of untreated mice (Office of Technology Assessment, 1990). Burton concluded that the study of the biological action and interaction of these components in mice suggests the existence of an inhibitory system involved in the genesis of tumors and capable of causing specific tumor cell breakdown.~In July 1985, Burton's Freeport clinic was suddenly closed by the Bahamian health authorities and the Pan American Health Organization on charges of contamination with HIV (then called HTLV-III) and hepatitis virus. Despite alarming stories in the media, no patient has yet been found who became HIV positive or succumbed to AIDS because of Burton's treatment. Investigations by the Immunoaugmentative Therapy Patients Association (now People Against Cancer) suggest that there may never have been any HIV contamination (Moss, 1989). Some 500 patients were receiving 8 to 10 injections per day; during the year after the clinic was closed, several hundred all tested negative for HIV (Wiewel, 1994). Additional standard HIV tests of serum and blood supply used to prepare the treatment were all negative as well.

The Freeport clinic, which reopened in January 1986 through the actions of Burton's patients and some members of the U.S. Congress, remains open at present despite Burton's death. More than 5,000 patients have received immunoaugmentative therapy in Freeport.

In spite of the many patients treated and the stories of remissions, extensions of life, and


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