Alternative Medicine:
Expanding Medical Horizons

A Report to the National Institutes of Health on Alternative
Medical Systems and Practices in the United States

Pharmacological and Biological Treatments

PANEL MEMBERS

Ralph W. Moss, Ph.D. -- Cochair
Frank D. Wiewel -- Cochair
Berkley Bedell
Richard A. Bloch
Seymour Brenner, M.D.
Stanislaw R. Burzynski, M.D., Ph.D.
James A. Caplan
Barrie Cassileth, Ph.D.
Peter B. Chowka
Serafina Corsello, M.D.
Harris Coulter, Ph.D.
Michael Culbert, D.Sc.
John M. Ellis, M.D.
Helga Fallis
Natalie Golos
Gary Johnson
Joseph Latino, Ph.D.
Floyd Leaders, Jr., Ph.D.
Edward Sopcak
John Stegmeier
Morton Walker, D.P.M.
Michael F. Ziff, D.D.S.

CONTRIBUTING AUTHORS

Ralph W. Moss, Ph.D.
Linda Silversmith, Ph.D.
Leanna Standish, N.D., Ph.D.
Frank Wiewel

Overview

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-to-date 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 understandably 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, double-blind, 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) 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._ 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._ 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._ 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 improvements in the quality of life, very little documentation exists of either the methods or the results of Burton's therapy. After the hostile reaction by the cancer establishment in the 1970s, Burton retaliated by withdrawing from his former colleagues and ignoring the basic requirements of scientific documentation. A standoff resulted, which OTA was unable to resolve. It is possible that the Freeport clinic, now led by R.J. Clement, and the other existing clinic in Germany will be more willing to cooperate in concrete studies and that serious investigations of immunoaugmentative therapy can now be launched.

714-X

The ideas of French-born Gaston Naessens are a controversial area on the fringe of modern medicine. Naessens, a microbiologist whose formal education was interrupted by World War II before he could earn an advanced degree, has proposed a theory that cancer cells are deficient in nitrogen and can become normal cells if they receive it. Naessen's treatment to provide the nitrogen is a mixture of camphor and nitrogen called 714-X. The camphor is present reputedly to help deliver the nitrogen when 714-X is injected into the lymph system in the region of the abdomen. Naessens also uses the treatment for AIDS. To find out whether the 714-X treatment is working, Naessens uses a special microscope that he invented, called a somatoscope. The somatoscope has been described as an altered dark-field microscope. Naessens claims it can visualize living things at magnifications unattainable through the ordinary light microscope. He monitors improvement in his patients by the status of their "somatids," variable particles that he has described in his viewings with the somatosocope.

In the 1980s in Quebec, Naessens was prosecuted for health fraud and threatened with life imprisonment. He was acquitted, however, after many people testified not only to his character, but also to beneficial results from using 714-X. Some of the individuals claiming cures for cancer and AIDS are quoted in Galileo of the Microscope (Bird, 1989).

Many Americans, including former congressman Berkley Bedell (Bedell, 1993), have used 714-X as an unconventional treatment for cancer._ It has penetrated a number of alternative clinics that concentrate on other treatments. Stories are circulating of dramatic improvements or, with AIDS, of conversion from HIV positive to HIV negative. However, Naessens has not published in peer-reviewed literature. Without impartial scientific evaluation, it is difficult to reach conclusions on his work.

Hoxsey Method

The Hoxsey treatments are among the oldest U.S. alternative therapies for cancer and have been some of the most controversial. Like Essiac (see next section), they use a mixture of powerful herbs. These mixtures were probably derived from early Native American Indian medicines, although that connection is not as well established as with Essiac. Some of the same herbs are included in the formulas for both methods.

In the early part of the century Harry Hoxsey, an uncredentialed layman, marketed several cancer treatments in his clinics across the South. He claimed his remedies had been passed down to him by his father and grandfather, and he kept the ingredients secret until 1950. Eventually U.S. authorities shut down Hoxsey's clinics, but the treatment is still available at the Bio-Medical Center in Tijuana, Mexico, which is headed by Mildred Nelson, Hoxsey's former nurse assistant. Hoxsey indicated that some of his herbal components were present to necrotize tumors and others, as purgatives, to carry away the waste.

Hoxsey's remedies basically consist of an external salve and an herbal potion. The external medicine is an escharotic--a kind of burning paste--composed of zinc chloride, antimony, trisulfide, and bloodroot; its purpose is to corrode cancers. The paste is used principally for skin cancer (usually basal cell carcinomas), and many ambitious claims have been made for it. However, few reports on its efficacy (or lack thereof) exist in peer-reviewed literature. Moh's micrographic surgery, an orthodox procedure that bears some relationship to the Hoxsey treatment, is cited (Swanson, 1983): Moh's method consists of the use of zinc chloride paste to "fix" the tumor in place; the tumor is then removed in a series of steps.

The internal medication, which is the primary concern here, is made up of various herbs added to a base of potassium iodide and cascara, which is a bark preparation. The principal herbs are pokeweed root, burdock root, barberry (Berberis), buckthorn bark, stillingia root, and prickly ash. As Patricia Spain Ward noted in a contract report to OTA for its Unorthodox Cancer Treatments project, many of these roots and barks are now known to have anticancer and immunostimulatory effects._ The following items discuss several:

* Pokeweed. Pokeweed root (Phytolacca americana) has several effects on the immune system including stimulation of the production of two cytokines (see the glossary), interleukin 1 (IL-1) and tumor necrosis factor (TNF) (Bodger et al., 1979a, 1979b). Boosting the immune system is generally thought to help the body fight cancer._ Although pokeweed root is poisonous, it apparently has been used without serious toxicity problems since the mid-18th century.

* Burdock root. Burdock root (Arctium lappa) contains what Japanese scientists have called the "burdock factor" (Morita et al., 1984), which is reputed to act as a desmutagen, that is, a substance that reduces mutations. Burdock also has been shown to inhibit HIV, according to the World Health Organization (1989). In Japanese and macrobiotic diets young burdock roots are eaten as a vegetable called "gobo."

* Buckthorn. Buckthorn contains emodin, which has shown antileukemia activity in the laboratory (Kupchan and Karim, 1976).

It is noteworthy that, despite intense opposition, the Hoxsey formula has persisted as a cancer treatment for almost 100 years (Chowka, 1985). Among numerous anecdotal accounts of its effectiveness, some are hard to dismiss out of hand; it therefore warrants investigation. Despite decades of controversy, no clinical trials have ever been performed by either supporters or detractors of the Hoxsey therapies._ But since the Hoxsey formula contains the poisonous substance pokeweed, testing the formula is also a public health concern.

Essiac

Like Hoxsey therapy, Essiac is an herbal treatment. Reported to be of Native American (Ojibwa) origin, it was first brought to public attention in 1922 by an Ontario nurse named RenJe Caisse (Essiac is Caisse spelled backward). Caisse was impressed by the case of a local woman who claimed to have been cured of breast cancer by a local Native American healer. Caisse set up a clinic in Bainbridge and treated thousands of patients before being shut down by the Canadian medical authorities in 1942. One problem was that Caisse never made the formula public during her lifetime (1888-1978).

In 1982 a Canadian government report concluded, "No clinical evidence exists to support the claims that Essiac is an effective treatment for cancer." Nevertheless, the relevant government agency, Health and Welfare Canada (equivalent to FDA in the United States), agreed to make this medication legally available to advanced cancer patients under Canada's Emergency Drug Regulations. It is currently produced as a trademarked product in Canada. This and other versions of Essiac are also widely available through the "cancer underground" in the United States.

There are several different Essiac products, each of which claims to be the one and only authentic Caisse formula. According to author Gary L. Glum, a Los Angeles chiropractor, authentic Essiac contains four ingredients: (1) sheep sorrel (Rumex acetosella); (2) burdock (Arctium lappa); (3) slippery elm inner bark (Ulmus fulva); and (4) Turkey rhubarb (Rheum palmatum) (Glum, 1988).

* Sheep sorrel. The main ingredient, sheep sorrel--not to be confused with the more readily available vegetable garden sorrel, also known as "sour grass"--contains vitamins, minerals, carotenoids, and chlorophyll, all of which supposedly have anticancer effects either directly or through immunological or antimutagenic activity (Moss, 1992). Sorrel was the basis of a celebrated cancer "cure" in Virginia in the 1740s, and as jiwisi it was a noted remedy of the Algonquin Ojibwa (Snow, 1993). In folk tradition it is reputed to have many other medicinal qualities as well.

Sorrel also contains generous amounts of oxalic acid as well as emodin, which has been shown to have "significant antileukemia activity" (see discussion of buckthorn in the "Hoxsey Method" section).

* Burdock. (See also the "Hoxsey Method" section.) That the two long standing remedies of Hoxsey and Caisse have burdock in common is suggestive, although both formulas were long held in secret, and it is unlikely that Hoxsey and Caisse communicated or even knew of each other's existence. Burdock has been shown to be bioactive in a number of experiments (Dombradi and Foldeak, 1966; Foldeak and Dombradi, 1964; Morita et al., 1984; World Health Organization, 1989).

* Slippery elm inner bark. Slippery elm inner bark was tested by NCI without producing any sign of anticancer activity. Slippery elm lozenges, powdered bark, and slippery elm extracts are often available in health food stores and catalogs, with a wide range of curative and restorative claims listed for them.

* Rhubarb. Rhubarb has been used in Chinese medicine since at least 220 B.C. It is believed to exert a beneficial effect on the liver and gastrointestinal tract. Rhubarb extract showed anticancer activity in the sarcoma 37 test system (Belkin and Fitzgerald, 1952). It contains rhein, an anthraquinone, which has been shown to have antitumor effects (Office of Technology Assessment, 1990).

Essiac is widely used throughout North America, although, unlike ushe of Hoxsey's formula, use of Essiac is not associated with any particular clinic (Snow, 1993).

Coley's Toxins

Like many of the other pharmacological and biological treatments, Coley's toxins have attracted considerable medical and political controversy. More than 100 years ago, a New York bone surgeon at Memorial Hospital, William B. Coley, was investigating new approaches to curing cancer after his surgery failed to save a 19-year-old cancer patient. Coley chose to buttress a patient's immune system by giving him a bacterial infection that would cause a high fever and potently mobilize the patient's immune system to fight the cancer cells. Today, Coley is widely recognized as the first pioneer of immunotherapy--an approach that was virtually unknown in the 1890s.

The preparations that Coley developed were a mixture of killed cultures of bacteria from Streptococcus pyogenes and Serratia marcescens. Although not all patients responded to Coley's toxins, his treatment is reported to have shown dramatic curative effects on various cancers for many patients (Coley, 1894). These results were documented by Coley's daughter, Helen Coley Nauts, in a series of articles and monographs (Nauts, 1976, 1982, 1989.) Helen Nauts also founded the Cancer Research Institute in New York in 1953; this institute devotes itself to "the immunological approaches to the diagnosis, treatment, and prevention of cancer."

Nauts's monographs outline remarkable cures from the use of Coley's methods. Lloyd Old, an immunologist at Memorial Sloan-Kettering Cancer Research Center and a colleague, wrote, "Those who have scrutinized Dr. Coley's records have little doubt that the bacterial products that came to be known as Coley's toxins were in some instances highly effective" (Old and Boyse, 1973).

Over the years, Coley's work led to other discoveries. For instance, in the course of work on Coley's toxins in the 1940s, M.J. Shear of NCI discovered lipopolysaccharide (LPS), a component of bacterial cell walls. By injecting LPS into mice previously treated with bacillus Calmette-GuJrin, Old discovered TNF (Old, 1987, 1988; Oettgen, 1980).

The original Coley formulas are no longer being used, even experimentally, in the United States. Until the 1980s, they were being tested at Temple University, Pennsylvania (Havas et al., 1958; Havas et al., 1990). In his 1990 paper, Havas pointed out that using purified LPS to evoke immune reactions is problematic because of its toxicity and proposed returning to a cruder mixture, a mixed bacterial vaccine similar to Coley's toxins. The research reported in that paper showed the mixed bacterial vaccine to have anticancer and immunostimulatory properties at nontoxic levels in animals with tumors. The authors concluded that the vaccine "compares favorably with other biological response modifiers."

Outside the United States, Coley's toxins are being used in Beijing Children's Hospital, the People's Republic of China, and Germany (K`lmel et al., 1991).

MTH-68

The MTH-68 vaccine is a form of immunotherapy that employs a little-known biological product against viral diseases and various kinds of cancer. Developed by L<szlo K. Csat<ry, a Hungarian-American physician who currently resides in Ft. Lauderdale, FL, MTH-68 therapy is based on the idea that certain nonpathogenic viruses can be used to interfere with the growth of cancer in humans and the activity of harmful viruses.

MTH-68 is a modified attenuated strain of the Newcastle disease virus of chickens (paramyxovirus). In poultry, it causes an acute, fever-causing, generally fatal disease. In humans, however, the worst it does is trigger an acute but transient conjunctivitis (pinkeye), but this side effect is rare (Moss, 1992).

While Csat<ry was searching for a virus that would be harmless to humans but would attack cancer viruses, it came to his attention that a chicken farmer in Hungary with advanced metastatic gastric carcinoma had undergone a complete regression of his cancer after his flock experienced an epidemic of Newcastle disease. Csat<ry published his early observation in the British medical journal Lancet (Csat<ry, 1971). In 1982, 1984, and 1985 he published study results and a general article on interference between pathogenic and nonpathogenic viruses (Csat<ry et al., 1982, 1984, 1985).

Researchers in Hungary--under the direction of Sandor Eckhardt, the 1990-94 president of the International Union Against Cancer and the director of the Institute of Oncology--completed a multicenter, Phase II, double-blind, placebo-controlled clinical trial with terminal cancer patients (Csat<ry et al., 1990; Moss, 1992). According to the statistical analysis in internal reports on the Phase II study, "the number of cases with stabilization or regression was significantly higher in the MTH-68/N group; favorable response in subjective parameters, such as pain relief, occurred in a significantly higher percentage in the MTH-68/N group; and performance status improved in the MTH-68/N group and significantly deteriorated in the placebo group."

Patients in Phase II received MTH-68/N by nasal drops or by inhalation (MTH-68/N is a live virus vaccine derived from the attenuated strain). The researchers say that the treatment has proved to be nontoxic and devoid of side effects. Currently, the Hungarian research team is still waiting for financial arrangements for Phase III trials.

A recently published report provides more details concerning the Phase II study (Csat<ry et al., 1993). The study subjects had advanced cancers with multiple and widely distributed metastases. The duration of the protocol was 6 months, but those patients who had reacted favorably to treatment were continued on therapy. Further evaluation about survival was done after 1 and 2 years.

There were 59 patients in the study--33 in the MTH-68/N group and 26 in the placebo group. Their tumor types included lung, pancreas, kidney, sigmoid colon, and stomach cancer. In the MTH-68/N group, 2 patients experienced complete remissions, 5 experienced partial remission, 1 had moderate remission, and 10 had stabilization, for a total of 18 positive responses. Median survival time was significantly extended beyond that of the placebo group, which had only 2 stabilizations.

In addition, 26 subjects in the MTH-68/N group versus only 7 in the placebo group had either unchanged or increased weight. In the MTH-68/N group, 15 subjects had a sense of better well-being, 13 reported increased appetite, and 11 reported decreased pain; no one in the placebo group reported these effects (Csat<ry et al., 1993).

Csat<ry is currently negotiating with an American biotechnology company to speed development in the United States, and he has expressed willingness to have OAM conduct clinical trials of his product. He does not treat patients in the United States. Csat<ry's explanation of how MTH-68 works is based on his belief that many human cancers are of viral origin.

Three possible mechanisms of antitumor action by the nonpathogenic avian viruses include direct cytolysis (cell killing), tumor-specific immune enhancement, and cytokine (see the glossary) stimulation. Thus, the avian viruses may modify tumor cells and enhance tumor-specific immunity (Schirrmacher et al., 1986). Or they may selectively kill cancer cells. Or they may stimulate a wide variety of cytokines (Csat<ry, 1986, 1989), such as TNF (Lorence et al., 1988), interferons (Wheelock, 1966), and interleukins (Van Damme et al., 1989).

Neural Therapy

Neural therapy is a healing technique for attempting to deal with chronic pain and other longstanding illnesses and conditions. It involves injecting local anesthetics into autonomic ganglia (nerve cell bodies), peripheral nerves, scars, glands, acupuncture points, trigger points (points that produce a sharp pain when pressed), and other tissues and anatomical sites. Though unfamiliar to most American practitioners--and therefore part of alternative medicine--neural therapy is apparently quite widely used in Europe, especially for the treatment of chronic pain. According to its advocates, such as the American Academy of Neural Therapy, this "gentle healing technique" can instantly and lastingly resolve chronic problems when correctly applied (Klinghardt, 1991).

The history of neural therapy began with the discovery of local anesthetics in the late 19th century. In 1883, the Russian physiologist Ivan Petrov (1849-1936) laid the basis for the entire field when he hypothesized that the nervous system exercises a coordinating influence over all organic functions. Before he developed psychoanalysis, Sigmund Freud (1856-1939) discovered the anesthetic effect of cocaine on mucous membranes. In 1890, abdominal surgery was first performed using a 0.2-percent solution of cocaine. In 1903, a French surgeon first employed cocaine as an epidural anesthetic.

One obvious problem with cocaine, however, was its potential to be addictive. In 1904, Alfred Einhorn discovered procaine (novocaine), still widely used in medicine. In 1906, G. Spiess observed that wounds and inflammations subsided with fewer complications if they were first injected with novocaine. In 1925, a French surgeon, RenJ Leriche, used this compound for treating chronic intractable arm pain. He called novocaine "the surgeon's bloodless knife." In the same year, two German physicians described another local effect, claiming that an intravenous injection of novocaine could abolish migraine headaches (Dorman and Raven, 1991; Dosch, 1984).

A key development came in 1940, when Ferdinand Huneke discovered an instant healing reaction--what is now called the "lightning reaction" or the "Huneke phenomenon." First, Huneke injected novocaine into the shoulder joint of a woman with a severely painful, frozen right shoulder, but without any beneficial local effect. Instead, unexpectedly, the woman developed severe itching in a seemingly unrelated and relatively distant scar on her lower left leg. On a hunch, Huneke then injected novocaine into the itching scar, and within seconds the woman obtained full and painless range of motion in her right shoulder. The woman's scar dated from an operation on an infected tibia (shin bone). Although the leg operation was a "success," the woman soon afterward developed the frozen shoulder on the opposite side of her body. The initial scar had become, in neural therapy terminology, an interference field (Huneke, F., 1950; Huneke, W., 1952).

By combining the use of local anesthetics with the treatment of such (inferred) interference fields, Huneke and colleagues created an entirely new healing system they called neural therapy (Dosch, 1985). Neural therapy is said to be widely used for pain control in Europe, Russia, and Latin America and by 35 percent of all Western German physicians.

At first sight, it seems improbable that a scar on the left leg could cause a pain in the right shoulder or be resolved by an injection of local anesthetic into a scar at a site so distant from the shoulder. Dietrich Klinghardt offers several possible explanations for this phenomenon (Klinghardt, 1991), including one that he calls the "nervous system theory." Klinghardt's teacher, A. Fleckenstein, demonstrated that normal body cells and cells in scar tissue have a different electric potential across the cell membrane. In cells that have lost normal potential, the ion flux across the membrane stops (Fleckenstein, 1950). This means that toxic substances and abnormal minerals build up inside the cell. In turn, the cell becomes unable to heal itself and resume normal functioning. Treatment with local anesthetic may help restore ion flux for 1 to 2 hours, which could be enough time for the cell to partially repair itself and resume normal activity.

Another theory is that scar tissue can become, in effect, a "battery" of about 1.5 volts in the body. This scar "battery" sends forth abnormal electrical signals that disturb the autonomic nerve fibers (which lack the protective myelin coating possessed by most other nerve cells in the body). This electrical abnormality can disturb the overall autonomic nervous system, leading to systemic, and often severe, bodily dysfunction.

Also proposed is what Klinghardt calls the "fascial continuity theory." According to this theory, the fascia, or sheaths of connective tissues, are all interconnected. If scar tissue is present anywhere in this system, fascial movement can become impaired. Klinghardt claims that back pain, for instance, can sometimes be completely resolved by injecting a local anesthetic (novocaine or lidocaine without epinephrine) into a scar, such as that from an appendectomy or gallbladder operation.

In addition to its antipain functions, neural therapy has been used to treat allergies, chronic bowel problems, kidney disease, prostate and female urogenital problems, infertility, and tinnitus (Brand, 1983), as well as other problems (Pischinger, 1991). Klinghardt contends that although many diseases and conditions can be successfully treated by a variety of healing techniques, some conditions can be treated successfully only with neural therapy.

If it is an effective method, why is neural therapy not more widely accepted in the United States? One explanation may be that it does not lend itself to a double-blind study. According to Klinghardt, "each patient with low back pain needs to be treated in a different way." In addition, neural therapy also requires a meticulous injection technique and detailed history taking, both of which are time-consuming.

Apitherapy

Apitherapy is the medicinal use of various products of Apis mellifera--the common honeybee--including raw honey, pollen, royal jelly, wax, propolis (bee glue), and venom. Various studies attribute antifungal, antibacterial, anti-inflammatory, antiproliferative, and cancer-drug-potentiating properties to honey (Science News, 1993). In China, for example, raw honey is applied to burns as an antiseptic and a painkiller. Recently, propolis (the bee product that cements a hive together) has been identified as containing substances called caffeic esters that inhibit the development of precancerous changes in the colon of rats given a known carcinogen (Rao et al., 1993). Preparations from pieces of honeycomb containing pollen are reported to be successful for treating allergies, and bee pollen is touted as an excellent food. This section focuses on bee venom to treat chronic inflammatory illness because of the popularity of this treatment and the availability of related research material.

That forms of apitherapy have been used since ancient times is not remarkable, because bees formed an important part of many early economies. Ancient writers as diverse as Hesiod (ca. 800 B.C.), Aristophanes (ca. 450-ca. 388 B.C.), Varro (166-27 B.C.), and Columella (1st century A.D.) all wrote on the cultivation of the hive, and Charlemagne (742-814 A.D.) is said to have had himself treated with beestings. The Koran (XVI: 71) refers to bee products in the following terms: "There proceeded from their bellies a liquor wherein is a medicine for men" (Kim, 1986). For apiculture and the scientific understanding of bees, real progress began about 100 years ago when physician Phillip Terc of Austria advocated the deliberate use of beestings in his 1888 work, Report about a Peculiar Connection Between the Beestings and Rheumatism.

Today's proponents of apitherapy cite the benefits of bee venom for alleviating chronic pain and for treating many ailments including various rheumatic diseases involving inflammation and degeneration of connective tissue (e.g., several types of arthritis), neurological disease (e.g., multiple sclerosis, low back pain, migraine), and dermatological conditions (e.g., eczema, psoriasis, herpesvirus infections).

In one sample description of the use of bee venom therapy, a physician reported anecdotally that among 128 patients with a wide spectrum of illnesses, all but 11 appeared to improve (Klinghardt, 1990). (Of the 11 who did not improve, 1 was worse and 10 were unchanged.) This report is typical of anecdotal apitherapy reports that begin with stories of beekeepers recounting various health improvements after receiving accidental multiple stings from their bees. Klinghardt's patients had diagnoses of gout, rheumatoid arthritis, fibromyalgia, spinal strain or sprain, spinal disc injuries, postlaminectomy pain, bunion, postherpetic neuralgia, incomplete healing of a fractured bone, intractable pain from large burn wounds, osteoarthritis, ankylosing spondylitis, vertigo, and multiple sclerosis. Earlier, Steigerwaldt and colleagues (1966) reported improvement among 84 percent of 50 cases of arthritis in a controlled study.

In contrast, interest in bees has been sporadic in conventional medicine, focusing mainly on three areas unrelated to the therapeutic uses proposed above. These areas are (1) the danger of hypersensitivity reactions, including anaphylactic shock, from the sting of insects of the genus Apis; (2) the use of bee venom itself as immunotherapy for allergic reaction to such stings, especially to prevent life-threatening anaphylactic reactions in adults; and (3) the danger of infants contracting botulism from ingesting raw honey--possibly one death every 2 to 5 years (Wyngaarden and Smith, 1988).

The modern movement promoting apitherapy is spearheaded by veteran beekeeper Charles Mraz of Vermont and physician Bradford Weeks of Washington State, assisted by other members of the American Apitherapy Society. They cite studies identifying various biological properties for semipurified fractions of bee venom and for more purified products to help explain the curative properties attributed to this venom. Table 1, adapted from Klinghardt (1990), summarizes these properties, which include pronounced anti-inflammatory, analgesic, and immunostimulatory properties.

The American Apitherapy Society contends that hypersensitivity reactions to bee venom therapy are very rare, occuring mostly from stings by related species but not by the honeybee. The procedures the society recommends include always testing a new patient first with a small amount of venom to look for possible allergic reactions and never using bee venom without an emergency beesting kit (containing epinephrine) available.

In practice, proponents say that the best results are obtained when there is a "good reaction"--considerable swelling and inflammation--at the site of sting. Mraz believes that the optimal means of delivering venom is through a hypodermic needle administered by a licensed physician. However, since most medical practitioners do not recognize the benefits of bee venom, practicing apitherapists almost always use "the original hypodermic needle developed by Mother Nature and the honeybee some 30 million years ago: the bee stinger." Procedures for obtaining and purifying venom have been developed, but of course this product in liquid or dried form costs more than using live bees.

The usual treatment involves stinging the patient at a specific site relative to the illness and repeating the stings over a period of time. For example, it is suggested that the venom be injected into arthritic patients at trigger points in a daily course of treatment that lasts 4 to 8 weeks. Proponents indicate that there are typical patterns of responsiveness, depending on the ailment. A 50-year-old patient with arthritis might note pain relief in 2 weeks, mobility in 3 weeks, and freedom from symptoms in 4 weeks (Weeks, 1994).

Research on bee venom has included studies of whole venom and venom products. For example, in the 1960s and 1970s, studies on bee venom to treat rheumatic diseases were conducted by William H. Shipman of the U.S. Navy Radiological Defense Laboratory, James Vick of the Walter Reed Army Hospital Medical Research Center, and Gerald Weissman of New York University Hospital and their colleagues, with funding by private and public sources. One finding was that whole bee venom could suppress the development of an induced arthritis in rats, although it could not alleviate the illness after it had started (Zurier et al., 1973). Treatment with separate fractions of bee venom had no positive effect.

In later studies in which the components of bee venom were purified further, the various properties, such as anti-inflammatory and antibacterial activity (see table 1), began to be associated with specific materials.

In a more recent study (Kim, 1992), a randomized, controlled trial was conducted comparing true honeybee venom therapy with a "sham" product for 180 patients suffering from chronic pain and inflammation; solutions were injected twice weekly for 6 weeks. Significant posttreatment reductions in pain and inflammation were recorded in the true bee venom therapy group and were maintained at 6-month followups.

The American Apitherapy Society endeavors to coordinate information on bee venom research. Starting with 100 citations 12 years ago, when patients in his medical practice first interested him in the subject, Bradford Weeks, the society's president, has now acquired more than 12,000 case reports on persons treated with bee venom (Weeks, 1994). Together, these 12,000 reports are the basis for the ongoing National Multicenter Apitherapy Study. Approximately 200 physicians and 200 beekeepers voluntarily contribute reports.

At this time, the database for the multicenter study contains mostly anecdotal information, such as "I had an illness; I was stung by bees; my health improved." As Weeks notes, there is no proof in such reports that a person really had the specified illness and really improved because of the bee venom treatment.

The American Apitherapy Society would like to obtain research funds to improve the collection of both retrospective (past) information and prospective (future) data. Funding could provide research staff to search out medical records for proof of illness, training for research staff and bee venom therapists on how to gather data, and support for statistical analyses.

Meanwhile, the multicenter study has in its database some 1,300 reports on patients with multiple sclerosis (subjectively reporting increased sensation and bowel and bladder control), 2,800 with rheumatoid arthritis, and other groupings of data on such problems as gout, viral illnesses, and premenstrual syndrome--nearly 100 percent of 40 women being treated for premenstrual syndrome by apitherapy became symptom free, according to Weeks (1993).

In some ways, apitherapy is a classic alternative therapy. It has ancient roots and, although discarded by mainstream medicine, has survived in folk practice.

Iscador/Mistletoe

Iscador is a liquid extract from the mistletoe plant (Viscum album) that has been used to treat tumors for more than 60 years (Hajto et al., 1990a). A complex mixture, iscador has two properties that are thought to make it effective against tumors. Iscador is cytostatic and sometimes cytotoxic--that is, it can stop cell growth, sometimes even killing cells. In addition, iscador has immunostimulatory properties, affecting the immune system. Two protein components of the mistletoe extracts appear to be the major active ingredients, viscotoxins and lectins (Jung et al., 1990).

The mistletoe lectins have been studied in more detail than the viscotoxins. In general, lectins are a group of sugar-containing proteins that are able to bind specifically to the branching sugar molecules of complex proteins and lipids on the surface of cells. Certain lectins have both cell-killing and immunostimulatory activity. Their toxic effect occurs because they can stop protein synthesis in cells.

Viscotoxins can kill cells but do not act on the immune system. They act by injuring cell membranes. Considering the toxic properties of both major active ingredients of mistletoe extracts, it is not surprising that mistletoe itself can be poisonous and that proponents of iscador provide cautions about how much to take.

One study examined a lectin from a proprietary mistletoe extract that has been reported to show ability to affect the immune system in rabbits (Hajto et al., 1989). When a tissue culture of certain white blood cells was exposed to this lectin, increased secretion of certain immune system products resulted, including TNF alpha and interleukins 1 and 6, which are cytokines (see the glossary). In turn, there was an increase in the number and activity of certain types of white blood cells. A corroborating increase was seen in cytokine levels in serum of patients after injection of lectin doses (Hajto et al., 1990b).

Both the cell-killing and the immunostimulatory activities of iscador could potentially affect tumor cells. Whether iscador is an appropriate treatment for cancer has been the subject of at least 46 published clinical studies (6 collective reports, 5 small historical studies, 9 large historical studies, 14 retrospective studies, 10 prospective studies, and 2 randomized studies), which were reviewed by Helmut Kiene (Kiene, 1989). None of the studies fit the format of a controlled, randomized, double-blind clinical trial (see app. F). Kiene points out that such studies would be difficult to do because visible local skin irritations appear early in mistletoe treatments; thus both patient and doctor would know about the treatment._

Of 36 studies that Kiene decided were evaluable, he reported that 9 showed positive, statistically significant effects against diverse cancers, including ovarian, cervical, breast, stomach (postoperative), colorectal, and bronchial cancers and liver metastases. Usually the effect was to lengthen the survival time of the patient, commonly measured as median or average survival time; in one study, a significant reduction in the use of painkillers and psychopharmaceuticals was observed (see the glossary). The reviewer noted that the effect of mistletoe therapy tended to appear in situations involving patients with advanced stages of disease rather than patients with less advanced illness.

The antitumor effects observed in these studies with people are supported by studies with animal tumors. Furthermore, except for skin irritations, few uncomfortable side effects are reported by patients. This finding contrasts with the discomforts associated with more traditional anticancer radiation treatments and chemotherapy.

Much of the previous research was conducted in Germany, and the lead organization for a new study is also based there. NCI's Physicians' Data Query index identifies this study as a Phase III randomized trial of adjuvant treatment with INF-A (interferon alpha) versus INF-G (interferon gamma) versus mistletoe extract (iscador M) versus no further treatment following curative resection of high-risk stage I/IIB malignant melanoma._ A three-volume compendium of research papers on iscador, including translations of some from German, is available (Scharff, 1991).

Revici's Guided Chemotherapy

Emmanuel Revici, a Romanian-born physician, is still practicing in New York City in his late nineties. (His license was suspended in November 1993, but that is being challenged.) Revici has developed an approach to illness (particularly cancers) that he calls biologically guided chemotherapy (Lerner, 1994; Revici, 1961). The basis of Revici's approach is a concept that disease involves a biological dualism. While in a healthy body anabolism and catabolism balance, in a diseased body their imbalance results in diseases that are either anabolic (see the glossary) or catabolic. Correspondingly, the way the diseased body responds to treatment differs depending on the type of imbalance. In their choices of therapies, physicians must therefore be guided by which condition predominates.

Revici ascribes the effects of tumor cells to lipid imbalances. If fatty acids predominate--a catabolic condition--the tumor tissues are described as having an electrolytic imbalance and alkaline environment. If, instead, sterols predominate--an anabolic condition--there is a reduction in cell membrane permeability, according to Revici.

The patients Revici determines to have a predominance of fatty acids are treated with sterols and other agents with positive electrical charges that can theorectically counteract the negatively charged fatty acids. If sterols are predominant, treatment is with fatty acids and other agents that can increase the metabolic activity of fatty acids. The determination of anabolic (rich in sterols) or catabolic (rich in fatty acids) character is based on a series of medical tests and judgments about body type. For example, a lean individual would be more likely to have a catabolic condition, and a rounded individual, an anabolic one; Revici also considers females more likely to have an anabolic character, and males, a catabolic one. Based on the various tests, an individualized chemotherapy program is designed for each patient with cancer. (This individualization makes it harder to conduct controlled studies of treatment effectiveness.)

Along with Revici's choice of type of lipid to administer, he may incorporate other materials, such as selenium, in his lipid envelope. According to his theory, the additional agent will be delivered ("guided") directly to the tumor site because of the site's affinity for the selected lipid carrier. Because of this specificity, lower systemic drug toxicity is expected.

OAM has expressed interest in an evaluation of Revici's approach as a cancer treatment. Besides anecdotal reports concerning Revici's patients, one independent clinical trial was already conducted by Joseph Maisin, director of the Cancer Institute of the University of Louvain, Belgium. Although the results were never published, Maisin is reported to have written to Revici that dramatic improvements occurred in 75 percent of 12 terminal cancer patients. These improvements included tumor regression, disappearance of metastases, and cessation of hemorrhage.

Revici has applied his dualistic theory to other conditions besides cancer. He first developed therapies for different kinds of pain. Among the other conditions he is reported to have addressed are itching, insomnia, vertigo, migraine, radiation burns, osteoarthritis, rheumatoid arthritis, convulsions, postoperative bleeding, AIDS, ileitis, colitis, and drug addiction.

Future Research Opportunities

In general, alternative biological and pharmacological treatments are a rich area for investigation. At this time, further research would be helpful in the following specific approaches.

* Antineoplastons. These should have high priority. Antineoplastons could be investigated through best case series and patient outcome methodology.

* Cartilage products. Simone's offer to perform a prospective study on shark cartilage is now being followed up, aided by his receipt of IND approval from FDA in early 1994. In addition, an evaluation of bovine cartilage (Catrix) should be undertaken.

* EDTA chelation therapy. The study of EDTA as chelation therapy that was dropped in 1991 should be resumed. However, since it is unlikely that a sponsor can be found, as an alternative OAM should consider less costly ways of testing EDTA chelation therapy. One might be to assemble from the research of physicians currently using it a best case series (see Appendix F) of patients who have allegedly benefited from it for occlusive heart disease and related conditions. A prospective outcomes study should be undertaken as well.

* Ozone. The data suggest that ozone may have some effectiveness with AIDS. Whether or not that is true, ozone should be evaluated for public health reasons because of its wide use among people with AIDS. Whether ozone has any anticancer effects, either in laboratory situations or in living organisms, should also be investigated.

* Immunoaugmentative therapy. Because of previous lack of documentation, a best case series (see app F.) should be assembled from cases treated, focusing on such intractable conditions as mesothelioma. An attempt should be made to document at least 10 indisputable successes. If these cases prove valid, a prospective patient outcomes study should be undertaken with self-selecting U.S. patients who are attending the immunoaugmentative therapy clinics in either Freeport (the Bahamas) or Germany.

* 714-X. 714-X should be investigated through best case reviews, field investigations, and, if warranted, clinical trials.

* Hoxsey method. The Hoxsey treatment should be investigated both because of numerous anecdotal accounts attesting to its effectiveness and because the formula contains the poisonous substance pokeweed and is therefore a public health concern. Outcomes research should be conducted on patients at the Bio-Medical Center in Tijuana to determine what results, if any, are being achieved and what side effects may occur.

* Essiac. Essiac is widely used throughout North America. An observational study of patients taking this medication should be arranged.

* Coley's toxins. These should have high priority. Investigation could be done either by reactivating the Temple University study or by sending an observation team to China (Guo Zheren, Coley Hospital, Beijing Children's Hospital, People's Republic of China) or to Germany (Dr. Klaus F. K`lmel, G`ttingen, Germany). H.C. Nauts and staff members at the Cancer Research Institute have indicated an interest in helping with any evaluation.

* MTH-68. This should have high priority. It shows promise as an innovative, nontoxic medication for various kinds of cancer and viral diseases. A possible approach is to join with the Hungarian scientists to initiate Phase III trials of MTH-68/N--trials that are now awaiting financial arrangements.

* Neural therapy. The literature should be studied, and a best case series should be assembled from cases treated. An attempt should be made to document at least 10 indisputable successes. If these cases prove valid, a prospective patient outcomes study should be undertaken with self-selecting patients.

* Apitherapy. Because of lack of documentation, a best case series should be assembled from cases treated. An attempt should be made to document at least 10 indisputable successes for each ailment treated. If these cases prove valid, a prospective patient outcomes study should be undertaken with self-selecting patients.

* Iscador/mistletoe. A best case series should be assembled from cases treated. An attempt should be made to document at least 10 indisputable successes. If these cases prove valid, a prospective patient outcomes study should be undertaken with self-selecting patients. The new multicenter European study should be monitored.

* Revici's guided chemotherapy. This should have high priority. A prospective clinical study of cancer patients should be evaluated.

Key Issues and Specific Recommendations

The following key issues and recommendations relate directly to the material in this chapter:

* Changes in regulations for FDA approval should be made if alternative pharmacological and biological treatments are to have a fair hearing.

* To prepare for innovative approaches, the director of OAM should work together with the FDA to develop a memorandum of understanding so that proposed trials that have been approved by OAM can proceed. FDA and State authorities should declare a moratorium on seizures, raids, import alerts, and licensing actions against physicians, researchers, and health care providers whose work has been chosen by OAM for evaluation. In 1992-93, the case of S.R. Burzynski was an urgent case in point (see the "Antineoplastons" section).

* In choosing specific treatments for testing, priority should be given to drugs and vaccines that address major causes of preventable death in the United States: cardiovascular disease, cancer, and AIDS. Priority should also be given to testing treatments that particularly show promise for safety and low costs. To gain public recognition and credibility, it is important that OAM achieve some clear successes.

---

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Table 1. Analysis of Bee Venom

Component_Action_Effect on pain/painful joint__

Hyaluronidase and isoenzymes_Depolymerizes hyaluronic acid (the "glue" of the body)._Allows other components of bee venom to penetrate deep into tissues, inside cells, and inside joints.__

Compound X_Lowers surface tension of all fluids (surfactant)._"Wets" cell walls with bee venom, allows better penetration.__

Phospholipase A (20% of venom)_Converts lecithin (from cell walls) into lyso­lecithin, which acts as emulsifier, causes hemolysis in high doses. Most toxic component of venom._Emulsifies debris within joints and other tissues, increases local pain briefly; counterirritant.__

Melittin--a major component of venom; a peptide containing 26 amino acids_Stimulates ACTH secretion in the pituitary (cortisol). Protects lysosomal membranes. Powerful antibacterial agent. Causes lysis of mast cells. Also may be membrane­active, superoxide­production­inhibiting enzyme._Strong anti­inflammatory effect and long­acting. Short­acting histamine effects--increased capillary permeability, edema, temperature elevation, itching pain, increased vitality and sense of well­being.__

Apamin--a peptide containing 18 amino acids_Stimulates central secretion of serotonin and dopamine. Blocks nerve signal crossings in periphery._Increases central and peripheral nervous system pain threshold; decreased pain, increased sense of well­being.__

Mast cell degenerating protein (also called peptide 401)_Strong anti­inflammatory action (approximately 100 times more than hydrocortisone)._Reduces inflammation and pain through local action on tissue inflammation.__

Other components____

Acid phosphatase, "­glucosidase, phospholipase B, several peptides_Inhibition of complement, kinines, proteases, substance P, and other effects._Anti­inflammatory, pain reducing.__

Source: Adapted from Klinghardt (1990).

Prudden noted in his report that he was providing data only on the 31 patients who "took Catrix consistently and followed instructions completely." If the number of patients who stopped treatment are included (approximately another 60 patients), the recalculated response rates (approximately 30 percent responding and 20 percent complete) are still satisfactory. However, cancer therapy studies usually deal with one type of cancer at a time, and Prudden's patients had at least nine different types.

Some other researchers are interested in ozone's ability to stimulate production of interferon (Bocci and Paulesu, 1991).

The quantity of CD4 cells, a type of white blood cell, usually decreases sharply as the condition of a patient with AIDS worsens.

Congressman Bedell previously had surgery and radiation treatment for prostate cancer. At public meetings and hearings, he attributes to 714-X the stopping of a recurrence of this cancer 2 years after surgery. (No medical confirmation of the recurrence has been provided publicly.)

Ward, P.S. 1988. History of Hoxsey Treatment (contract report for the Office of Technology Assessment).

For example, the Merck Manual (Berkow, 1992) indicates that "the presence of immunogenic surface structures on human neoplastic cells permits their recognition by immunocompetent host cells as well as their interaction with humoral antibodies."

Indeed, Patricia Ward notes in her research paper that the American Cancer Society listed Hoxsey's remedy in 1971 on its unproven methods list without citing any research basis for this listing.

However, such a study is not impossible. A control treatment could be used that also produced a (harmless) rash. In fact, this suggestion is made in the "Research Methodologies" chapter in a section discussing appropriate research designs. However, as Kiene (1989) cautions, local irritants are immunostimulatory; it would be necessary to make sure that their actions were strictly local.

The protocol number is EORTC-DKG-80-1, and the NCI file entry was last modified in November 1993. The lead organization is the European Organization for Research on the Treatment of Cancer (EORTC) Melanoma Cooperative Group of Hamburg, Germany, with the first participant listed as U.R. Kleeberg of Haematologisch-Onkologische Praxis Altona. More than 20 European centers are involved in this trial, including hospitals in Germany, Austria, Belgium, Estonia, France, and Switzerland.

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