Physician Survey of Male and Female Physicians Confirming Their Willingness to be Doctornauts

Physician Survey of Male and Female Physicians Confirming Their Willingness to be Doctornauts

Because of my particular interest in carnitine and the urgent need to conduct more clinical research on natural substances, in 1983, FIM conducted a survey on 2,100 male MDs, 500 female MDs, and 500 DOs potential doctornauts asking the following question: “Would you as a physician-patient want the privilege to volunteer for clinical research of natural substances under the supervision of a physician-clinical researcher without FDA, institutional or other restraints?”

Over 50% in each category responded in the affirmative! But here’s another encouraging finding. We called about 100 doctors asking the same question but adding, “if you had a disease such as Alzheimer’s or another disease or disability,” would you volunteer? Almost 100% said they would! This entire experience is described in my book, From Oysters to Insulin: Nature and Medicine at Odds.”

Stephen L. DeFelice, M.D.

Carnitine – Doxorubicin Clinical Study for the Treatment of Stages III-IV Ovarian Cancer

CARNITINE- CANCER SUMMARY

Carnitine – Doxorubicin Clinical Study for the Treatment of Stages III-IV Ovarian Cancer

BRIEF HISTORY

Carnitine is a naturally occurring safe substance found in most human cells. Orphan Drug NDA approvals of both the intravenous and oral forms were obtained by Sigma tau, Inc. a U.S. subsidiary of the Italian Company, Sigma tau S.p.A, for the Orphan Drug indications of primary and secondary carnitine deficiency as well as renal dialysis.

Carnitine has a number of actions. The two primary ones are the transport of fatty acids across mitochondrial membranes where they are metabolized to produce ATP and reducing or eliminating the toxic effects on the mitochondria by a wide variety of substances. There are a substantial number of preclinical and clinical publications to support these actions.

During the Vietnam War Major James Vick and I were stationed at WRAIR, the Walter Reed Army Institute of Research. He was a cardiovascular pharmacologist specializing in shock research, including those caused by toxins, and I, based, on my ongoing basic and clinical research experience with carnitine, was highly interested on its general shock reversal potential. At that time the government was-and, more than ever, still is – interested in a number of toxins for both medical and national self- defense reasons. The Major and I decided to conduct a number of preclinical cardiovascular studies. Parenterally administered carnitine successfully prevented and treated myocardial ischemia, cardiac arrhythmias and congestive heart failure all of which findings have been subsequently confirmed and published in both preclinical and clinical studies. Cardiac carnitine levels are reduced in these states causing mitochondrial dysfunction. The administration of parenteral carnitine replenishes cellular levels restoring normal mitochondrial function and ATP production.

Regarding our studies on the toxins, E.coli toxin, Kussell snake viper toxin, coral palytoxin and doxorubicin (Adriamycin), carnitine was given as treatment after lethal, shock producing doses were in effect. The administration of carnitine dramatically reversed all shock states.

The doxorubicin- induced acute shock state was primarily due to cardiotoxicity. We then wondered whether carnitine also blocked its cell kill capacity. In otherwords, it was a general inhibitor of doxorubicin. Fortunately, one of our colleagues, Sam Barranco, was a well respected cancer researcher with expertise in cell culture technology. He evaluated this possibility using Chinese hamster ovarian culture cells. Carnitine not only did not block doxorubicin’s cell killing capacity but synergistically increased it tenfold!

For a variety of reasons the major one being the lack of strong patents, it was difficult was to convince a pharmaceutical company to sponsor a clinical program to obtain an NDA. Time passed and, sparked by my experience of a 24 year old woman diagnosed with ovarian cancer, I decided to test the combination of the two drugs in human ovarian cancer culture cells because this is a preclinical model that is predictive of doxorubicin’s clinical efficacy.

The study was conducted at Vanderbilt University Medical Center. The results were extremely encouraging. Carnitine not only increased the cell killing capacity of doxorubicin but, surprisingly, also had a significant cell kill capacity of its own. It killed over 50% of the cells at dose levels which can be safely achieved in patients by intravenous administration.

Over the years I had lost contact with the carnitine cancer literature. When I called my long time friend and colleague, Dr. Claudio Cavazza, the proprietor of Sigma tau S.p.A, I discovered he had already supported a number of cancer related laboratory studies on carnitine and its relatives. Results were encouraging and dependent on the laboratory model. But the net effect was unequivocally positive regarding enhanced tumor cell kill capacity as well as anti- toxicity effects on chemotherapeutic agents.

CARNITINE’S MECHANISM OF ACTION

In a number of laboratory studies carnitine has been shown to induce apoptosis in cancer cells while having no effect on normal ones. There are two primary theories of carnitine’s anti-cancer activity which application depends on the type of cancer cell. One is based on data reporting that cancer cells limit the utilization of mitochondrial fatty acids as a fuel. Carnitine, which transports fatty acid across mitochondrial membranes, increases the fatty acid fuel supply to the cancer cells having a detrimental effect on the malignant cell leading to increased apoptosis.For example, in human colon cancer cells, carnitine increased fatty acid uptake resulting in a significant increase in apoptosis. No effect of carnitine on normal colon cells was found.

The second theory holds that carnitine induced apoptosis is related to a mitochondrion-dependent and death ligand/ receptor-dependent pathway. In mouse hepatoma cancer cells carnitine significantly induced apoptosis while it had no effect on normal cells.

There are other theories. For example, in breast cancer tumor bearing mice it is believed that cancerous mitotic activity is dependent on increased arginase and decreased nitric oxide activity. The administration of carnitine decreased arginase and increased nitric oxide activity while significantly decreasing mitotic counts.

Regarding carnitine’s ability to dramatically reduce doxorubicin’s cardiotoxicity as well as enhancing its tumor apoptotic activity, there may be two different mechanisms of action involved. In the non- malignant Chinese hamster cells, carnitine had no effect but when given with doxorubicin there was a synergistic apoptotic effect which bespeaks of one type of mechanism. When given to human ovarian cancer cells carnitine has its own significant apoptotic effect. When given with doxorubicin in this model it did increase the former’s apoptotic effect but not synergistically which raises a number of possibilities.

CARNITINE STUDIES DEMONSTRATING THAT CARNITINE BLOCKS DOXORUBICIN’S CARDIOTOXICITY

Since Major Vick and I conducted the first experiment observing that carnitine impressively blocked doxorubicin-induced cardiotoxicity there have been dozens of preclinical studies, acute, subacute and chronic, which have confirmed our findings.

There are a number of clinical studies which, mainly employing the EKG and blood enzymes, which report that carnitine blocks the acute cardiac effects of doxorubicin. It, however, is commonly accepted that these acute effects are not predictive of the ones that lead to chronic cardiomyopathy.

Though not definitive in design, there is one clinical study evaluating forty patients with non-Hodgkin’s lymphoma that addresses the latter possibility. Echocardiography was employed to evaluate cardiac function. There were no deleterious changes over a three month period in those treated with carnitine and doxorubicin. In addition, molecular mitochondrial measurements supported these findings. Both mitochondrial RNA and oxidation were increased.

CARNITINE’S RELATIVES AND OTHER CHEMOTHERAPEUTIC AGENTS

There is the possibility that carnitine may also increase the anticancer activity of other chemotherapeutic agents. For example, acetylcarnitine (ALC) and proprionylcarnitine (PLC) are mostly converted to carnitine. In mouse leukemia which is resistant to mitoxantrone, ALC alone had no effect but when given with mitoxantrone it significantly prolonged survival time. PLC increased the anti-cancer activity of taxol when administered to mice with breast cancer tumors.

CLINICAL STUDIES REPORTING CARNITINE DEFICIENCY IN BOTH ADULT AND PEDIATRIC CANCERS

In an adult population of cancer patients with fatigue, 78 percent of this population was reported as carnitine deficient. In a pediatric cancer population it was reported that carnitine deficiency exists and is not due to dietary input but to the cancer process itself and/or chemotherapeutic treatment. These findings indirectly support the preclinical results that carnitine deficiency may play a role in increased apoptotic malignant cell proliferation as well as contribute to the toxic effects of chemotherapeutic agents.

CARNITINE’S BROAD ANTI-TOXICITY PROFILE VERSUS ITS ANTI-CANCER ONE

It is interesting to note that the results of studies that evaluated the anti-toxicity properties of carnitine are consistently positive while those evaluating it anti-cancer effects- whether alone or in given with chemotherapeutic agents- depend on the type of cancer and the experimental model used. In addition to the toxins evaluated by us at WRAIR some other examples are that carnitine blocks the toxicity of formaldehyde, diphtheria, methotrexate, AZT (zidovudine) and carboplatinum. The most reported beneficial effects have been on cardiac and neuronal cells. The same holds true with ALC and PLC.

Toxins, either directly or indirectly, negatively impact mitochondrial function. Carnitine’s dual mechanism of action on the mitochondria most likely accounts for its anti-toxicity activity.

There is then this intriguing possibility: in certain malignancies carnitine may have an a) anti-toxicity effect but not an anti-cancer one or b) both types of activity. In addition, the data indicates that the anti-cancer dose of carnitine is significantly higher than the anti-toxicity one which may explain the differences in activity. This possibility must be considered in clinical studies.

From a clinical point of view, in the preclinical models carnitine is effective both as treatment and prevention. Because carnitine is a generic drug it is highly improbable that a costly, long term clinical prevention study will be done. Generally speaking, treatment studies, however, are much less costly and can be done relatively quickly. Since carnitine is already an FDA approved drug with an enviable safety profile, and since there are millions of cancer patients living with the toxic effects of chemotherapeutic drugs, an interested clinical investigator would find it less difficult to take the treatment approach.

THE ONGOING CLINICAL STUDY WITH CARNITINE AND DOXORUBICIN IN STAGES I-IV OVARIAN CANCER

This patient population was selected based on a number of complex factors. Bottom line, we are searching for an obvious effect in a small, specific cancer patient population. If carnitine is found to be effective in these patients, then it will hold promise for others. The patient population chosen are those in late stages of ovarian cancer where cancer cells have become resistant to platinum-taxane therapy a small percentage of whom, however, are known to respond to doxorubicin. The study has recently begun and patient recruitment is ongoing.

RATIONALE FOR THE HOPE

The hope is based on six points: The first is that in this population though minimal, there is a tumor size reduction response to doxorubicin. The second is based on the unique synergistic effect of carnitine on doxorubicin’s cell kill capacity in Chinese hamster ovarian culture cells. The third is based on carnitine’s impressive apoptotic effect on human ovarian cancer culture cells. The fourth is based on doxorubicin’s cell killing effect on human ovarian cancer culture cells which is a model that is predictive of the drug’s effectiveness in clinical studies. The fifth is based on the carnitine’s ability to increase the tumor kill capacity of doxorubicin in these same cells. The sixth is that both the reduction of toxicity and increased tumor cell apoptosis may enhance the effectiveness of the immune system and other body defenses.

Stephen L. DeFelice, M.D.

February 1, 2009

ENCLOSURES

A review of carnitine’s clinical cardiovascular profile by Dr.

Carl J. Pepine entitled, “The Therapeutic Potential of Carnitine in Cardiovascular Disorders”. Though it was published in 1991, and more positive clinical studies have followed since then, this review covers carnitine’s broad

clinical potential including doxorubicin cardiotoxicity.

Chinese hamster ovarian culture cell abstract.

Vanderbilt Human ovarian cancer culture study.
Fatty acid proposed mechanism of action – the human colon cancer cells.
Mitochondrion and death ligand proposed mechanism of action- mouse hepatic cancer cells.
Chronic preclinical studies demonstrating carnitine’s ability to block doxorubicin’s toxicity.
Clinical study on patients with non-Hodgkin’s lymphoma demonstrating that carnitine block’s doxorubicin’s cardiotoxicity as well as corrects doxorubicin-induced mitochondrial toxicity.

Acetylcarnitine- mitoxantrone.

Proprionylcarnitine- taxol

Low carnitine levels in adult and pediatric cancer patients.
Examples of carnitine’s broad anti toxic activity are AZT, methotrexate, carboplatinum, formaldehyde and diphtheria toxin.
Protocol of the clinical study.
Carnitine package inserts, Sigma tau-Carnitor, for the intravenous- oral forms.

Promising Opportunities for Doctornauts

Promising Opportunities for Doctornauts: Exploring Gangliosides and the Carnitine-Doxorubicin Combination in Ovarian and Other Cancers

By Stephen L. DeFelice, M.D., Founder and Chairman | March 24, 2025

On the FIM home page a Doctornaut is described as a physician who is substantially freer to volunteer for clinical studies. This would include the vast world of substances without patents such as natural substances. As a result, the cornucopia of promising new therapies would be tested for their clinical effectiveness, a significant percentage of which will be available much sooner than usual. Also, the discovery of cures and low-cost therapies will result in the reduction of healthcare costs beginning in the short term.

Take the GM1 ganglioside as a doctornaut opportunity. Gangliosides are natural substances found in neurons that create nerve growth or sprouting. Now, there are many neurological diseases and injuries in which nerves are damaged and die (apoptosis). But normally, because of the high costs and risks to obtain FDA approval for a single disease or condition, a company would choose to develop GM1 for a single disease or condition, provided, of course, it has sufficient product ownership such as a strong patent. But if doctornauts were available, many health organizations and small groups covering a broad range of neurological conditions from spinal cord injury to stroke to degenerative diseases, among others, would—patent or no patent—sponsor small probing clinical trials designed to detect clinical activity in a relatively brief period of time instead of years—if, of course, doctornauts were available.

Carnitine and doxorubicin offer another opportunity for doctornauts. Doxorubicin is an extremely broadly effective anti-cancer drug. The dose, however, is limited because of its cardiotoxicity. During the Vietnam War, while at WRAIR, the Walter Reed Army Institute of Research, cardiovascular pharmacologist James Vick and I teamed up and demonstrated that carnitine blocks doxorubicin’s cardiotoxicity, which has been substantiated by others. This offered the clinical promise that the dose of this chemotherapeutic agent could be raised, thereby increasing its efficacy. Working with others, it was shown in laboratory studies that the combination of carnitine and doxorubicin was effective in various neoplastic models, but carnitine itself had an apoptotic or killing effect on ovarian cancer cells.

I ran into a stone wall in an attempt to demonstrate this effect in a clinical study until I succeeded in obtaining approval at St. Joseph’s Hospital in New Jersey in 2007. But the physicians refused to subject their ovarian cancer patients to enter the study. The following is the rationale that was presented to the hospital committee, but more general studies, including clinical, have been published since:

Summary of the Rationale of the Carnitine-Doxorubicin Combination for the Treatment of Ovarian Cancer presented to St. Joseph’s Hospital Committee for Study Approval (IRB) (Ovarian Cancer Summary)

Now, just imagine if the St. Joseph’s study was conducted in 2007 and confirmed that the combination was extremely effective. How many ovarian cancer patients would have benefitted, and suffering avoided? Also, imagine if women doctornauts existed, and the aforementioned happened much sooner?

Physician Survey of Male and Female Physicians Confirming Their Willingness to be Doctornauts

In my next post on the Nutraceutical Research and Education Act or NREA and the Doctornaut Act, I will describe my collaboration with then Senate Majority Leader Bill Frist on the Doctornaut Act and how, with our booming technology including AI, doctornauts can jump-start the discovering of medical breakthroughs, including cures—and how those breakthroughs can reshape healthcare.

TIME TO CORRECT THE EPISTEMOLOGIC CHAOS THAT PREVENTS NUTRACEUTICAL CLINICAL DISCOVERY

October 12, 1999

What is Health?
What is Disease?
What is a Health Claim?
What is a Medical Claim?

Stephen L. DeFelice, M.D.

The current nutraceutical (foods, medical foods and dietary supplements) industry is market-driven, but needs to become research-driven. Nutraceutical companies sponsor very little clinical research to evaluate the efficacy and safety of their commercialized products, and few realize that their present and future success requires that they start proving what they are claiming.

Why is this happening? Mainly because current federal laws and regulations have created epistemologic chaos regarding certain nutraceutical definitions. These faulty definitions are applied by the FDA and then serve to limit the freedom of companies to make legitimate medical or health claims. It is, therefore, crucial that we resolve this epistemologic dilemma in order to form a rational foundation for new Congressional laws that will encourage nutraceutical clinical research.

For example, current laws such as DSHEA mistakenly attempt to distinguish the difference between a health and medical claim. If, for example, a nutraceutical dietary supplement lowers cholesterol and a company makes such a claim, it is considered a medical and not a health claim and, therefore, not permitted to be made by the company. The company may be permitted to claim, “it benefits the body’s cholesterol” in order to be considered a health claim.

The ultimate result is that the truth – that the product does lower cholesterol – cannot be claimed by a company. A misleading cholesterol claim, however, can be made. This common type of epistemologic chaos borders on sophistry and is clearly unacceptable. It both robs the patient of important truthful information concerning his or her health and also profoundly discourages nutraceutical clinical research, the essential element in medical discovery, be it for the management of a disease or abnormal condition.

There is an urgent need for Congress to pass new laws which contain new, precise language defining such critical terms as health, disease, health claim and medical claim. This will allow and encourage companies to conduct nutraceutical clinical research on products that will help to reduce or eliminate disease, the manifestations of disease or other abnormal conditions, premature death, and yes, health care costs.

The four core questions to be answered are as follows:

1. What is health?
2. What is disease?
3. What is a health claim?
4. What is a medical claim?

In addition to having queried various experts on these questions, I turned to both lay and medical dictionaries for enlightenment. The following are representative definitions which are in harmony with those of the experts:

American Heritage Dictionary:

HEALTH:
1. The state of an organism with respect to functioning, disease and abnormality at any given time.
2. The state of an organism functioning normally without disease or abnormality.
3. Optimal functioning with freedom from disease and abnormality.

Stedman’s Medical Dictionary:

HEALTH:
The state of the organism when it functions optimally without evidence of disease or abnormality.

American Heritage Dictionary:

DISEASE:
An abnormal condition of an organism or part, especially as a consequence of infection, inherent weakness, or environmental stress, that impairs normal physiologic function.

Stedman’s Medical Dictionary:

DISEASE:
Morbus; illness; sickness; an interruption, cessation, or disorder of body functions, systems, or organs.

In FDA’s recent attempt to define “disease”, it states that the latter is “any deviation from, impairment of, or interruption of the normal structure or function of any part, organ, or system (or combination thereof) of the body that is manifested by a characteristic set of one or more signs or symptoms, including laboratory or clinical measurements that are characteristic of a disease.”

This definition is an exercise in classic tautology. Basically, it states that a disease is a disease which is not very helpful in clarifying epistemologic chaos. If FDA had added “or abnormality” at the end of the definition after” disease” then it would be in harmony with the experts, lay and medical dictionaries. (To further complicate the issue, it is possible that FDA may be applying this definition of disease to dietary supplements only and not to other categories such as foods.)

What is very encouraging and surprising is the basic commonality and consistency of the perception of the meaning of “health” and “disease”. Both make good sense because they reflect the truth of reality.

Regarding the term “health”, both dictionary definitions describe two conditions – “disease” and “abnormalities”. Neither tries to distinguish the difference between the two. For example, few would call a sore knee after playing tennis or periodic fatigue or PMS diseases. But they are indeed abnormal conditions which often, like disease, require medical management. After all, a problem is a problem no matter what you call it.

Regarding the term “disease”, the words “disorder of body functions” and “abnormal condition of an organism or part….. that impairs normal physiologic function” certainly includes a sore knee, periodic fatigue and PMS, none of which is commonly perceived as a disease. Cutting through all the complexities of both medical and lay dictionaries, be it a specific disease or a specific abnormal condition, both types of entities are commonly referred to in general definitions of health and disease. In order to be healthy, we must be free of disease and any other abnormal condition. For complex historical reasons, the simplicity of this self-evident truth has eluded us.

In the final analysis, we must ask ourselves what is important to the patient. This fundamental principle is too often forgotten. If a patient has either PMS or pancreatic cancer, the patient needs medical management. Giving a condition a name and categorizing it with a legal-regulatory label is academic and does not meet the real needs of real people. What is important is whether therapy will benefit the patient and not fruitless epistemologic debates, particularly when such debates powerfully discourage clinical research on nutraceutical discovery.

Considering the aforementioned and using common sense, I would propose the following four definitions:

1. Health is the absence of disease or any other abnormal condition which may generally, but not always, require medical management.

2. Disease is a condition that impairs health and could benefit from medical management.

3. A health claim deals with a substance that has a beneficial clinical effect on a disease or abnormal condition.

4. Similarly, a medical claim deals with a substance that has a beneficial clinical effect on a disease or abnormal condition.

In conclusion, it follows that there is no difference between a health and medical claim.

Congress must act now on FIM’s proposal, the NREA (Nutraceutical Research & Education Act), which was introduced in Congress by Representative Frank Pallone (D-NJ) on October 1, 1999. The NREA permits companies to make claims based primarily on the results of the clinical research conducted on the specific product commercialized. If a nutraceutical lowers cholesterol, then the claim should reflect the truth, i.e., it lowers cholesterol. If a nutraceutical decreases insomnia, then the claim should reflect it. No distinction is made between a health or medical claim.

If we are compelled to continue to categorize claims, we should replace the terms “health” and “medical” claims. Instead we should use a new term, “medical-health” claims as the legal and regulatory language of choice.