Orphan Drugs – Chapter 3
The Carnitine Story
The long story of carnitine has a clear message: It is almost impossible to develop a natural substance for clinical use in the United States without resources equal to those of the pharmaceutical industry or the government.
The barriers to clinical research involve risks, costs, and frustrations that only the patience of Job and the wealth of Rockefeller could overcome. There are strong forces working against innovation. Ironically, they are academic medicine, the health industry, and the federal government, all of whom profess to represent the patient. In different ways, each force effectively blocks the development of new ideas. Without grants, academicians are poorly motivated. The health industry is listless and led by lackluster physicians and scientists. The government is callous to the conditions which make entrepreneurial discovery in medicine possible.
The essence of discovery is to have an idea and to test it. In medicine, the test of an idea comes in clinical research and human experimentation. Block experimentation in humans, and innovation is lost. The ultimate loser, of course, is the patient.
I was 28 years old when I first postulated that carnitine might be effective in the treatment of myocardial ischemia. I was 41 years old when the first clinical trial showed this hypothesis to be correct. It took 13 years, even though carnitine is an extremely safe, natural compound, even though I am a specialist in clinical drug development, and even though I know many leaders in the pharmaceutical industry and in academic medicine.
The carnitine story began in 1964, when a major American drug company encouraged me to take a fellowship in clinical phammacology at St. Vincent’s Medical Center in New York City. At that time, a French phammaceutical company had asked the American company whether it had any interest in the possible antihyperthyroid activity of carnitine. Since thyroid disease was one area of my expertise, they asked me to evaluate carnitine in hyperthyroidism. Three patients with classic hyperthyroidism were chosen for the initial study. During the first week of carnitine administration, all three became clinically euthyroid, and there was a concomitant fall in pulse rate-a remarkable achievement in this patient population. Surprisingly, thyroid function tests were unchanged, indicating that carnitine was not acting on the thyroid gland but was acting peripherally. I submitted the results of the study to a few journals, but the report was rejected for publication because only a subjective observation confirmed that a therapeutic event had occurred. With the impatience of youth, I became angry, arguing that even an effective antigravity pill could not be proven to the satisfaction of the Journal of the American Medical Association unless the upward distance traveled by the volunteer was precisely measured. The subjective observation that he, like Elijah, was rocketing toward heaven would not be sufficient for publication. The effort having proved futile, I went on to the next logical step, a clinical trial to obtain objective data. The American company had established a sophisticated clinical research unit in a prison, and there, after administering thyroid hormone (triiodothyronine) to volunteers, we measured whether carnitine would alter the effects of exogenous thyroid hormone on blood lipids and other parameters. Carnitine did alter certain effects. We published both the subjective and the objective data, but, strangely, endocrinologists still have not recognized these studies (1,2).
During the clinical trial one patient with angina was inadvertently placed in the carnitine group. He told me that, for the first time in years, his angina had significantly diminished. At the time, I did not pay much attention to his comments, but they made a lasting impression.
Reviewing the literature did not help me explain the antithyroid activity of carnitine, but I found that carnitine enhanced the entry of longchain fatty acids into mitochondria, where they are metabolized. The byproduct of this metabolism is biological fuel. Theoretically this should worsen the hyperthyroid state, since it might produce excess energy. While trying to understand why increased fatty acid utilization should improve hyperthyroidism instead of exacerbating it, I suddenly remembered the enthusiastic prisoner with angina pectoris. I excitedly postulated that carnitine could increase the fuel supply to the heart under ischemic conditions, permitting myocardial tissue to function normally under pathological conditions. There was also another possibility: Carnitine could exacerbate anginal symptoms by stimulating the heart to work harder. But the solitary prisoner whose angina had improved was sufficient for me to disregard the exacerbation possibility. There is nothing like an empirical observation to win the day over theory.
Early the next morning, with a feeling of excitement and adventure, I began to plan tests of this theory. I did not know that it would take almost 13 years before it could be successfully tested in patients. I never dreamed that even after demonstrating a clinical anti-ischemic effect, I would be without a financial sponsor.
What is carnitine? Carnitine is a naturally occurring quaternary amine found in most mammalian tissue but present in relatively high concentrations in skeletal muscle and heart.
The physiological role of carnitine was first studied in the 1930s. In the late 1940s, Fraenkel found it to be a necessary dietary constituent for the growth of the meal worm, Tenebrio molitor (3). It was designated Vitamin BT (for Tenebrio). The first observed mammalian function was that carnitine increases the rate of fatty acid oxidation in rat liver homogenates. More recently, the importance of carnitine for the oxidation of free fatty acids and their utilization within human myocardium has been elucidated.
During the past 15 years, numerous preclinical studies have demonstrated that carnitine has a wide spectrum of pharmacologic actions in various cardiovascular models. The cardiovascular properties of carnitine can be divided into two broad categories, those related to myocardial ischemia and those apparently not related to ischemia.
Myocardial ischemia. The force of contraction and the heart rate are dramatically reduced in the ischemic Langendorff heart preparation; adding carnitine almost totally blocks these ischemic changes (4). Palytoxin, an extract of soft coral from a South Pacific island, is a potent coronary artery vasoconstrictor which consistently causes fatal myocardial ischemia in dogs a single dose of carnitine reduces mortality by approximately 50%, by preventing the myocardial ischemic changes that lead to ventricular fibrillation and cardiac arrest (5). In several other animal studies, carnitine consistently reduced the severity of ischemic changes when it was administered either prophylactically or therapeutically (6-8).
Other cardiovascular properties. Carnitine improved left ventricular function in dogs injected with high doses of diphtheria toxin, and reduced the mortality produced by diphtheria toxin in guinea pigs (9,10).
In isolated perfused rat heart deprived of essential nutrients, myocardial function is significantly impaired. When added to the perfusate, carnitine aided the recovery of such hearts after they had been taken to the point of exhaustion. The effect of carnitine was more pronounced than that of glucose or insulin (11). At high doses, carnitine increased heart rate and force of contraction in anesthetized dogs and pigs (12). These effects were not antagonized by either reserpine or propranolol.
In isolated dog heart-lung preparations, congestive heart failure can be produced by increasing venous return and aortic resistance. Carnitine increased cardiac output and left ventricular force in these preparations, thereby relieving pulmonary edema (13). In isolated Langendorff heart preparatins, propranolol significantly reduces contractile force and heart rate. However, when carnitine was administered before propranolol, it significantly decreased propranolol’s cardial depressant effect (14). It is interesting that when administered at the same doses after propranolol has exerted its depressant effect, carnitine’s effect is less dramatic.
Carnitine demonstrates antiarrhythmic activity in electrically induced atrial fibrillation (15). In cats, carnitine raised the electrical threshold for arrhythmias, an effect that was more pronounced with the addition of atropine.
Carnitine was compared with ouabain in anesthetized dogs that had developed severe heart failure after electrical stimuli were applied to the atria to induce atrial flutter and ventricular arrhythmias (16). Carnitine had significantly greater activity than ouabain on force of contraction, cardiac output, and cardiac work. The antiarrhythmic activity of carnitine was also markedly superior to that of ouabain.
A single dose of carnitine administered after the onset of endotoxic shock reversed the shock and greatly improved the survival rate in dogs given doses of Escherichia coli endotoxin (17). In another dog experiment, involving lethal doses of Russell’s viper venom, carnitine also dramatically increased survival (18).
Tricyclic antidepressant drugs are known to cause cardiac abnommalities. Carnitine significantly reversed the ECG changes induced by nortriptyline in rabbits (19). In addition, carnitine has been shown to block the cardiac toxicity of both adriamycin and daunomycin, two highly effective antineoplastic agents, without interfering with their antitumor activity.
Very few compounds offer the promise shown by carnitine in these preclinical studies. What can explain the almost universal lack of interest in a drug with such obvious potential? In the beginning, the data were unpublished. Academicians find it difficult to accept data unless they have been reviewed and published by a reputable journal. The pharmaceutical industry, on the other hand, rarely gave a reason for its lack of interest. Occasionally a manufacturer would cite the lack of a patent or the weakness of use patents as the main reason for rejection. The government has no mechanism for helping individuals develop new drugs, and the foundations lack expertise and perhaps sufficient will.
Another reason for the lack of interest was carnitine’s broad spectrum of activity. Most scientists are able to accept and understand a new antibiotic because the prototype of this class of drug has been studied and the ground rules for product evaluation have been clearly established. The NIH (not invented here) syndrome is not a joke. For psychologic and political reasons, institutions are highly resistant to outside ideas. Scientists repeatedly seek funds for their own projects and resent diversion to other projects in which their personal interests are not best served. Finally, the pharmaceutical industry in the United States (unlike that in Europe) is not interested in natural substances as potential therapeutic agents. They have been enthralled by the wonders of synthesis, losing sight of the fact that natural substances have already established an impressive track record for creating life and combating disease.
Carnitine was caught in these “Catch 22” events. Because the preclinical findings were so promising and so broadly applicable, the disbelief was greater. The lack of published studies in reputable journals compounded this disbelief, but I was advised not to publish the data since I could not obtain patents once the information was in the public domain. After 5 years of this frustrating impasse, I decided to become a businessman and to obtain a patent so that the carnitine data could be published.
Then came the surprise. It was impossible to obtain a strong patent for carnitine because it is a natural substance. The only possible patent was a “use” patent. This means that if a patent was obtained for the use of carnitine in the treatment of myocardial ischemia, then no one but the patent holder could manufacture and sell carnitine for that use in the United States. If, however, someone discovered that carnitine was also good for headaches, then another use patent could be obtained for that use. That patent holder would also have the right to manufacture and sell carnitine. Even if a manufacturer did not obtain a patent, he would be free to sell carnitine for the treatment of headache since he would not be promoting it for myocardial ischemia. He could charge a substantially lower price than the pharmaceutical company that had invested in carnitine’s development and, obviously, hospitals and pharmacies would buy the cheapest carnitine and use it for all indications, not only headache. A pharmaceutical company is loath to invest in the development of a product without some guarantee of financial return on the investment. There was no such guarantee with carnitine.
In order to arouse interest in this country, I decided to file an investigahonal new drug (IND) application on carnitine. An IND permits clinical trials with an investigational substance. Information regarding the production, quality, and stability of the substance in addition to detailed toxicologic and pharmacologic data in various species are needed for an IND. The amount of data required depends on the nature and duration of the intended clinical trial. There was a substantial difference between the cost of opening an IND using oral administration and that of an IND using only intravenous administration. The latter is cheaper. I also hoped that an answer regarding the efficacy of carnitine could be obtained in a shorter period of time using intravenous carnitine in acute clinical models.
Even the lower cost of the intravenous effort proved too expensive for me. To compound the problem, while the literature contained references to animal toxicity, the studies had not been performed in accordance with present standards. Since I could not afford to conduct acceptable toxicity studies, I decided to formulate a strategy that would eventually allow me to open the IND. The strategy was as follows:
1. Acute animal toxicity studies would be performed in the United States.
2. A phase I trial would be performed abroad, but it would conform to FDA standards.
3. For the first clinical trial in the United States a disease would be chosen that was life threatening, for which the effectiveness of available therapy was questionable, and for which carnitine held some promise. In this way, trivial governmental objections would be waived.
4. After the IND was opened, a U.S. company would be sought to sponsor a phase II trial to discover the proper indications for carnitine.
5. Financial support would be obtained to help accomplish these goals.
At the suggestion of Jim Rand, I flew to Germany to meet with the owner of a large pharmaceutical firm. The owner, against the recommendations of his research staff, graciously granted me $15,000. This grant allowed me to continue the preclinical studies and to start two clinical studies, a phase II trial in Costa Rica and a phase I trial in Yugoslavia. Since carnitine is extremely safe, I decided to cut through the red tape and go directly to phase II trials to find an indication as quickly as possible, thereby avoiding the ponderous steps awaiting me in my own country. Unfortunately, the Costa Rica project never quite got off the ground. In Yugoslavia, at the University of Ljubljana, Dr. Stoyen Jeretin conducted a phase I trial using intravenous carnitine (20). Production difficulties with the intravenous dosage form proved to be another roadblock. My colleague, Dr. Joseph Thomas, temporarily lost his sight from conjunctivitis after exposure to ultraviolet light in the sterilization of carnitine. Dr. Stephen Steen of the University of California, Los Angeles, agreed to fly to Yugoslavia to collaborate on the phase I study with Dr. Jeretin. Dr. Steen is a friend and a superb investigator. He and Dr. Jeretin each gave themselves the highest doses of carnitine, and each developed significant phlebitis. After their experience, my associate, Dr. Neil Sanzari, and I diluted the carnitine solution with distilled water and injected it intravenously into ourselves. Irritation did not result, and this dilution was used in future studies.
To gain support for the IND, I asked several highly regarded academicians to review the carnitine data to determine the most appropriate clinical indications for evaluation in the United States. Endotoxic shock and the prevention of adriamycin-induced cardiac toxicity were selected. Since endotoxic shock is associated with a very high mortality, and since known therapy was of questionable value, I decided to use this indication to open the IND. The next step was to find an investigator.
I solicited the support of a friend and one of the great men of medicine, Dr. Joseph DiPalma. With his generous help, an investigator was found and the IND was submitted to the Food and Drug Administration.
International trials were initiated with the expectation that a “hit” would be made during the early phases which would be useful in expediting clinical trials in the United States. A water-soluble compound with a broad spectrum of activity in preclinical models, I reasoned, was almost guaranteed to have activity in at least one clinical model. Alas, logic and reality do not always walk hand in hand. Carnitine’s initial clinical trials demonstrated no clear-cut activity. Preliminary studies with the intravenous dosage form in Europe and South America in patients with ischemic heart disease, congestive heart failure, and shock did not show dramatic activity. There was little reason to doubt the results. The international investigators who performed these studies were competent and sincere in their effort to evaluate carnitine objectively. There were two possible explanations: either the clinical models were not appropriate or carnitine is a placebo. I could not, of course, accept the latter. One important finding of these trials, at least, was confirmation of the clinical safety of this natural substance. Unlike most cardiovascular pharmacologic substances, carnitine has a wide margin of safety.
The obvious choice, a definitive clinical trial in patients with myocardial ischemia, was impossible because the clinical model for evaluating a drug in myocardial ischemia was angina pectoris. This would require an oral dosage form of carnitine. The preclinical, clinical, and manufacturing costs to produce an acceptable oral dosage form were staggering. The door was effectively closed because of regulatory agency requirements.
Suddently, camitine’s luck improved. I met the entrepreneurial president of a relatively small U.S. phammaceutical company which was without a director of research. He made a personal decision to invest in carnitine. He listened, obtained a few opinions, and decided to sponsor initial, probing trials to determine whether intravenous carnitine would be clinically effective. The additional funding he provided was sorely needed, and the company also packaged carnitine solution in sterile vials according to modern regulatory standards. This temporarily removed the FDA as a possible obstacle regarding objections to the manufacturing and control of the intravenous dosage form.
The initial clinical trials were not promising. In patients with congestive heart failure, intravenous carnitine produced only a 20% increase in cardiac output (21). Patients with ventricular arrhythmias resistant to known therapy also failed to respond to carnitine (22). No clinical pharmacologic effect was observed in patients with coronary artery disease or cardiac myopathy given carnitine in doses of up to 9 g by catheter directly into the right atrium (23).
After this lackluster performance, only an extremely biased supporter could continue to be optimistic about this drug. A single case of endotoxic shock maintained my optimism. Carnitine had a definite vasopressor effect in a patient who had responded poorly to dopamine (24). In all truth, however, disappointment and frustration hallmarked this dark period. The paradoxical success of continuing carnitine studies conducted by Major Vick and others in experimental animal models added to this frustration. A decision was made to investigate the obvious indication of myocardial ischemia. The problem continued to be the lack of an acceptable oral carnitine preparation.
While the phase II trials were proceeding, the sponsoring company hired a director of research who, as one of his first acts, recommended that the company terminate its carnitine agreement. The director never consulted or contacted me regarding this decision. Left with little choice, the president informed me of the decision to terminate-another setback in the carnitine story.
The clinical program could not be continued without another investor. Fortunately, we were consultants to a large chemical company that was determined to enter the pharmaceutical field. After presenting the carnitine story, the man responsible for the pharmaceutical venture promptly signed an agreement to support the ongoing clinical program. There was no director of research at that time. The two companies that invested in carnitine were remarkably similar: in each a businessman made the decision to support and in each a director of research was not an obstacle. I dreaded the day when a director of research would enter the chemical company. Deep within, I feared that history might repeat itself.
During this period, I reamed that Drs. Austin Shug and James Thomsen- of the University of Wisconsin had requested the intravenous dosage form of carnitine from a drug supplier. Out of curiosity, I met with them at the Chicago airport. Drs. Shug and Thomsen were the first academic carnitine enthusiasts I had met, and they strongly recommended that a cardiac atrial pacing study be done in patients with angina. I preferred other clinical models, believing that the atrial pacing model would fail. However, Shug and Thomsen did not reveal all their data at our first meeting. They had discovered that after ligating coronary arteries in the dog, naturally occurring carnitine is acutely depleted from the ischemic portion of the myocardium. Under normal conditions, the myocardium uses fatty acids as the preferred fuel, but during ischemia the myocardium switches to glucose, a less efficient fuel. When carnitine was administered under ischemic conditions, Shug and his associates found that carnitine was quickly absorbed by the ischemic portion, with reversal of the ischemic changes. Atrial cardiac pacing, therefore, was a logical model: it simulates the acutely stressed, ischemic myocardium that still has sufficient blood flow to deliver carnitine.
We agreed to do the study. Using the atrial pacing technique, Thomsen et al. showed that the hearts of patients with angina pectoris or ischemic heart disease could be paced longer and faster with carnitine than with placebo (25). This supported the hypothesis that ischemia produces acute carnitine deficiency. The atrial pacing data were confirmed by two additional acute clinical pharmacologic models (26, 27).
Dr. Silvio Garattini of the Mario Negri Institute in Milan found that the normal rat myocardium does not easily take up carnitine (28). Unlike the situation with propranolol, digitalis, or other cardiovascular drugs, it was theorized that a deficiency of carnitine must exist before its activity could be demonstrated. This explained why the resting patients with coronary artery disease did not respond to 9 g of carnitine. There was no carnitine deficiency because there was no acute ischemic stress.
After the initial atrial pacing study had been completed, a distinguished group of experts was assembled to assess the data. They concluded that Dr. Thomsen’s work supported the efficacy of carnitine in the treatment of myocardial ischemia. The favorable report was submitted to the sponsoring company. The company had recently hired a new director of research, who read the positive report and then, without warning, promptly terminated the carnitine contract shortly before Christmas 1976.
Without support the clinical program came to a virtual standstill. Attempts to find another pharmaceutical company to assist the carnitine effort failed. One encouraging aspect was the gradual respect that carnitine was earing in the pharmaceutical industry and academia. This was largely due to the publication of the data in accepted scientific and medical journals. To complicate the patent problem, I was warned that use patents are usually not issued in foreign countries. A foreign firm would agree to market the drug only if the carnitine data were not public and not available to other companies. Foreign companies needed “lead time in the marketplace.” Unfortunately, this attitude also prevailed in this country. Although industry scientists in the United States now believed that carnitine had therapeutic potential, the lack of a strong patent and the availability of published data weighed against an investment. I believed, and still believe, that this attitude about a substance with carnitine’s potential is incorrect.
Ironically, I succeeded in licensing carnitine to two European companies; one company did little work and subsequently can celled our agreement, but the other, Sigma-Tau, of Rome, Italy, responded with miraculous vigor. The owner and president of Sigma-Tau, Dr. Claudio Cavazza, was convinced of carnitine’s potential after an hour-long discussion with me. The discussion was certainly refreshing, because I did not encounter the profound resistance to new ideas that characterizes the U.S. industry. There is an interesting contrast between a president who owns the company and has the power to make crucial decisions and the president of a U.S. firm who is predominantly a manager, dependent on committees and individuals to present him with the information for decision making. Decision by committee is laborious and promotes internal political struggles over the act of weighing the data. Facts are lost or buried without having seen the light of reason.
In the carnitine story, 1978 was a good year.
Shortly after Cavazza decided to develop carnitine in certain countries abroad, I contacted a U.S. company that, surprisingly, showed interest in licensing the parenteral dosage form in the U.S. And a venture capital group approached me, offering a large sum of money to form a new company that would eventually offer shares to the public. At that point, Cavazza became interested in developing carnitine in the United States.
I was surprised and pleased to have three interested parties at one time -more in l year than in the previous 12 years. After some soul searching, I chose Sigma-Tau as the appropriate partner. The U.S. company was a bit too timid about investing sufficient capital to develop carnitine. Its position was:
How can we justify to our stockholders the expenditure of large sums of money for a substance with a poor patent position? How would our management look if we spent millions of dollars to develop carnitine only to have another company obtain FDA approval for carnitine for a single indication not covered by our use patent and sell it at a very low cost to everyone for every indication? We would have to substantially reduce our price. In other words, we do all the work, we take the risk, and another company without research and development costs enters the market with little financial risk and beats the hell out of us.
I listened carefully and received a lesson in economics. I didn’t totally agree with the reasoning, but the company was certainly right about most substances with poor or absent patent protection. Since there would be insufficient funds to develop carnitine, there was no alternative but to reject the company’s offer.
I did not accept the offer from the venture capital group, even though I was initially excited about forming a company that would create “carnitine-fever” on Wall Street. In venture capital endeavors, profit is the primary objective. All else is secondary. A good public relations effort could periodically cause the marketplace to tingle, thereby raising the price of the stocks but making the investors lose sight of the original objectives. In addition, I would have to interact constantly with the venture capitalists to justify expenditures. In my heart I am a capitalist, but in this case my primary goal is to bring carnitine expeditiously into the physician’s armamentarium. I rejected the offer and chose instead to collaborate with Cavazza and to form a new U.S. company, BioCarn.
Forming BioCarn was a strenuous effort, complicated by scientific and economic considerations. One of our first decisions was to proceed with L-carnitine in an early phase II program evaluating carnitine in a broad variety of indications. Only a mixture of D- and L-carnitine had been used clinically. We chose L-carmitine because it is the natural form. However, there was a problem, since no one was producing the pure L-form. Cavazza decided to establish a method for large-scale production of Lcarnitine. On the surface, this appeared easy, but it was not. Production idiosyncracies delayed the initiation of clinical trials for almost a year.
To complicate matters even further, there has been a recent flurry of interest in carnitine in the academic world. Because of its action on fatty acid transport, the final product of which is energy, it is not surprising that carnitine has a broad spectrum of activity. I recall postulating that carnitine would be effective in various types of muscle disease, aging, and a host of other diseases. My friends would frequently smile, nod their heads in agreement, and rapidly change the subject. Presently, indications for its possible use include muscular dystrophy, renal dialysis, hyperlipidemia, and total parenteral nutrition. These developments require frequent reassessment of the clinical and economic strategy. In one sense, these developments are exciting, but in another sense, they continually disturb the course we have laid out for carnitine. Now and then, relaxing with cognac snifter in one hand and cigar in the other, I imagine what life might have been if carnitine was a simple substance with a strong patent position and only a single indication. It would long ago have been on the market, and my life would be less difficult and more secure.
During the past 10 years, 22 U.S. and 11 international companies have been approached regarding carnitine. This effort must approach a record in the annals of the pharmaceutical industry. After submitting the data to a company, only rarely did anyone ever contact me to discuss carnitine. The final decisions were invariably made without questioning and probing for the complete picture. Occasionally, after the rejection, I discovered that the reasoning behind the decision had been questionable and might have been corrected by a single telephone call. For example, one director of research and development told his management that he had no doubt that carnitine would be effective, but that the market potential would be very small. Myocardial ischemia, very small? Another director recommended rejecting carnitine because he and his staff agreed that it would require 6 years before carnitine could be marketed. This is, in my opinion, a miscalculation. For intravenous carnitine, a natural and safe substance that is effective for a significant indication, 3 years seems a more accurate prediction. These and many other objections could have been resolved by verbal communication before the final decision was made. Consider this absurdity: Patent lawyers from one very large and prestigious pharmaceutical company were quite impressed with the strength of the use patents, whereas another company’s patent lawyers labeled the use patents “worthless.” On the basis of the latter evaluation, carnitine was rejected even though the scientific staff had given a favorable report. To compound my frustration, no one asked me to respond to the patent lawyers’ opinion.
All in all, the industry’s decisions about carnitine were based on incomplete evaluations and lack of inquisitiveness. The lesson to be reamed is that the U.S. pharmaceutical industry is no longer entrepreneurial. The innovator must look elsewhere.
Strangely enough, the FDA was not the major force inhibiting the clinical evaluation of carnitine. To be sure, the regulations themselves were and are major forces delaying carnitine’s progress. FDA personnel, however, did not impose excessively stringent demands. I met with them and explained my situation. I told them that carnitine had great therapeutic potential, but I had little money to perform the usual preclinical studies required by the FDA. Drs. Belton and Crout of the FDA listened but made no promises. For whatever reason, the FDA did not raise excessive objections during the early clinical trials.
With a safe, natural substance such as carnitine, I should have been able to initiate clinical studies at least 5 years sooner. But the cost of complying with the FDA regulations was prohibitive. During the early carnitine research, I was a captain in the U.S. Army, with about $2000 in savings. This was quickly spent to purchase carnitine and experimental animals, and to pay miscellaneous expenses, such as travel and honoraria. In the end I had personal expenditure receipts for the carnitine venture of about $60,000. When I moved to a new home, most of these receipts were lost, leaving me without legitimate tax deductions. Another painful event in the carnitine saga.
Though FDA requirements proved to be expensive obstacles, on the scale of retarding factors, the major force against innovation has been the academic community.
Because I was struggling with a potential major breakthrough in the treatment of cardiovascular disease, it was logical to turn to cardiologists who are armed with remarkable equipment for measuring cardiac metabolism and function with precision. I believed that it would be easy to arouse the interest of several members of this dynamic specialty to test a safe, natural substance that could treat-or perhaps prevent-the disease most frequently confronted by cardiologists: myocardial ischemia. I prepared for a deluge of requests from cardiologists to supply them with carnitine for clinical evaluation. The deluge never came.
At least 50 academic cardiologists were approached, but with the exception of Dr. Shug and Dr. Thomsen, none became enthusiastic. The resistance of cardiologists to new ideas parallels that of the pharmaceutical industry and government. First of all, cardiologists are too busy to test a new substance. They concentrate on the heart as a pump and prefer to evaluate routine drugs, such as digitalis, utilizing a new gadget to measure cardiac output. There are economic rewards for this activity in the form of grants or their equivalent.
The brutal truth is that an academic would prefer to study a well-established effect of a wellestablished drug using a well-established technique for a $50,000 grant, rather than to evaluate a potential breakthrough in medicine for only $5000. Time and time again, the cardiologists listened, received their honoraria, and walked away. Potential investigators would invariably say, “Let someone else test it first. If the results are positive, then we’ll do it”; or, “Go abroad, produce some clinical data, and then come back,” or, the remark that I came to expect and the one that bothered me the most, “Why don’t you send over some carnitine and, for a small grant, we’ll evaluate it in our in vitro or animal models?” Now and then, a cardiologist offered to test carnitine in preclinical models at no cost. Without these gestures, I would have become a total cynic.
Academics are also self-righteous, I reamed. About 5 years ago, a distinguished group of authorities, cardiologists and other specialists, gathered in my office to review carnitine. The chairman of the group, an outstanding physician with a brilliant career in cardiology, had a special interest in myocardial ischemia. Questions regarding the lack of some pharmacological data characterized the meeting. “Why weren’t standard dose-response studies performed in dogs?” I answered, “Because each dog costs over $100, and I didn’t have the money at the time.”
When I said, “I believe carnitine should be evaluated in patients with preinfarction angina or myocardial infarction,” I received a curt and almost accusatory response. “It would be immoral,” the distinguished cardiologist answered, “and if you pursue this line of reasoning, I’ll leave the room.” If there had been any sign of open-mindedness, I would have pointed out the morality of the study I was proposing. If I had a safe, natural substance that unequivocally protects the ischemic heart, it would be immoral not to administer the substance to a patient with this condition. The benefits of carnitine in myocardial infarction have not yet been evaluated, but the rationale for its use is persuasive. I often wonder what magic trick or piece of information could suddenly change the immoral act to a moral one. Is it moral to condemn patients to die because of timidity and self-interest? Morality in research comes from weighing potential risk against the ability to conquer disease. If an answer is possible, if it is based on a strong experimental background, it is immoral to sit too long observing an everincreasing tide of morbidity and mortality.
Among all the delays and frustrations, one chapter in the carnitine story is the most depressing. It demonstrates the worst characteristics of our anti-innovative system-the story of adriarnycin.
Adriamycin, an anthracycline antibiotic, has antineoplastic activity against a variety of animal and human cancers. Some of the most serious side effects with adriamycin are related to its cardiotoxicity. Cardiomyopathies have developed which can progress to congestive heart failure and death. Reducing the dose of adriamycin reduces the incidence of cardiac problems, but its effectiveness as an antineoplastic drug is also reduced. A single intravenous injection of adriamycin can evoke serious cardiac arrhythmias, as shown in animal studies. Further, changes in coronary blood flow in monkeys have been demonstrated after administration of the drug in doses equivalent to those used in the treatment of acute leukemia.
With these problems in mind, studies were initiated to determine if carnitine might prevent the toxicity of adriamycin while retaining its clinical efficacy. If carnitine worked, higher and more effective doses of adriamycin could be used in cancer chemotherapy.
Adriamycin was used to produce deleterious cardiac effects in 40 isolated perfused Langendorff heart preparations (29). When injected directly into the coronary circulation, adriamycin consistently produced arrhythmias, decreased heart rate and force of contraction, and sharply elevated coronary perfusion pressure. Pretreatment with carnitine significantly inhibited the cardiac effects of adriamycin.. The sharp increase in coronary perfusion pressure previously observed in hearts exposed to adriamycin was not evident in those pretreated with carnitine. In addition, the sharp, progressive decline in force of contraction and heart rate and the ECG abnormalities were prevented. All 20 hearts pretreated with carnitine continued to function normally for as long as 4 hr after drug injection; those hearts given only adriamycin failed within 15-30 min. In approximately 50% of the heart preparatins not pretreated with carnitine, arrhythmias were noted within 5 min after adriamycin. These arrhythmias were not noted in any of the preparations pretreated with carnitine.
The next study evaluated the effects of adriamycin and carnitine on cardiac function in 10 adult rhesus monkeys (30). In 5 monkeys carnitine was injected intravenously 10 min before adriamycin administration. A single intravenous dose of adriamycin produced cardiac abnormalities in all 5 monkeys not given carnitine. Bigeminal and multifocal ventricular arrhythmias were consistently noted within 5 min after adriamycin and lasted for 60 to 120 min. Changes in heart rate and respiration were variable during the first 2 hr, while blood pressure was significantly reduced in 4 of the 5 monkeys. One monkey died at 90 min of apparent cardiovascular failure. These results are in striking contrast to those observed in the 5 monkeys pretreated with carnitine. In only 1 of these were arrhythmias observed, and the arrhythmias were of short duration. None of the monkeys in this group died.
The effects in acute toxicity models had been promising, and carnitine’s effect on adriamycin toxicity in subacute models was the next step (31). One study concluded that there were no differences between the adriamycin and the adriamycin-carnitine group, but only two animals were evaluated in each group. The study had other shortcomings and should not have been published.
In a more recent and more thorough study, the authors reported (32):
We have studied the potential drug interaction benefits of carnitine pretreatment of adriamycin toxicity in normal and leukemic mouse tissues…. Carnitine treatment significantly increased mouse survival at 60 days following acute or chronic adriamycin administration when compared to controls. Results of preliminary electron microscopy studies suggest that carnitine decreased adriamycininduced myofibrillar disruption, the number of mitochondrial aggregates and electron dense lipid-like bodies. Carnitine treatment may prove an effective prophylaxis against adriamycin cardiotoxicity in mouse and man.
Finally, in a study that is still in progress, 12 adult rhesus monkeys were used to study the possible beneficial effect of carnitine on the cardiotoxic properties of adriamycin (33). Of these monkeys, 6 served as controls and were given adriamycin every week for 3 months. All 6 monkeys developed progressive cardiotoxicity, including premature ventricular contractions, extrasystoles, and bigeminal pulses beginning at approximately 6 weeks posttherapy and becoming very severe at approximately 3 months. The other 6 monkeys treated simultaneously with carnitine and adriamycin showed no cardiovascular changes either at 6 weeks or at 3 months. None of the 6 camitine-treated monkeys evidenced physical deterioration such as was observed in the monkeys receiving only adriamycin.
Since carnitine inhibits the cardiac toxicity of adriamycin, it might inhibit adriamycin’s antineoplastic effect, thus nullifying any potential therapeutic combination. This possibility was evaluated in cell culture experiments (34). Carnitine added to the cells 1 hr before or in combination with adriamycin administration had no blocking effect on adriamycin’s cytotoxic activity. Carnitine administered 1 hr after cell exposure to adriamycin also did not block adriamycin activity. In fact, carnitine enhanced the cytotoxic properties of adriamycin. At this time, there is no explanation for this observation.
In another experiment camitine had no effect on adriamycin uptake into mouse atria (35). In mice bearing an intramuscular Lewis lung tumor carnitine did not alter the uptake or disappearance of adriamycin in heart tissue, lung tumor tissue, or serum of the mice (36). Further, carnitine did not reduce the tumor cell killing activity of adriamycin in systems in vitro and in vivo (37). In conclusion, the preclinical data indicate that carnitine does not inhibit tumor uptake of adriamycin or adriamycin’s tumor-killing properties.
Some additional work has been done to assess whether carnitine would inhibit the cardiotoxicity of daunomycin, an antitumor drug closely related to adriamycin. In a series of 20 isolated perfused Langendorff preparations, daunomycin consistently produced ventricular arrhythmia, tachycardia, and severe arrhythmias (38). After 30 min of severe arrhythmia, carnitine was administered and the arrhythmias were eliminated in 18 of the 20 preparations. The arrhythmias did not reappear for up to 90 min. In monkeys carnitine effectively reversed daunomycin-induced cardiac arrhythmias and no toxic manifestations were noted (39).
The data can be summarized as follows:
1. Carnitine significantly inhibits the cardiac toxicity of adriamycin. In addition, carnitine in acute, subacute, and chronic preclinical models increases the survival time of mice and monkeys treated with lethal doses of adriamycin.
2. Carnitine does not affect adriamycin uptake in cardiac or other tissues.
3. Carnitine does not block the antitumor activity or adriamycin.
4. Preliminary preclinical studies indicate that carnitine inhibits daunomycin-induced cardiac toxicity.
Carnitine, for all these reasons, is a leading candidate to be given along with adriamycin or daunomycin to block their cardiac toxicity and to permit larger doses of these antitumor drugs to be administered, thereby killing more cancer cells and increasing the chances of patient survival. One would expect that the phammaceutical industry, government, and academicians would jump for joy to have a substance with this potential available for testing. However even these data were not of interest to them. The government informed me that they had other priorities; the pharmaceutical companies wished me well and the academicians, as usual, walked away.
When Jim Vick and I first decided to evaluate carnitine and adriamycin, we did it out of curiosity. When we obtained positive results, we were surprised. We decided we could not stop, even without support. Adriamycin was not yet approved for use in the United States, and, in any case, we were not considering economic gain. Now the U.S. market for adriamycin is substantial, which makes pharmaceutical companies’ lack of action all the more puzzling.
But more than puzzling, this lack of action affects the survival of Americans. To this day, we cannot explain why the potential benefits of the camitine-adriamycin combination have not signaled a call to arms from the academic, pharmaceutical, and governmental communities. In my opinion, Congressional hearings have investigated scandals of lesser magnitude, and carnitine’s history should be the subject of a hearing. Patients are more concerned about getting well than about free health care. If more imaginative clinical research were supported, the resulting innovation could bring the new therapies we all need.
Where will carnitine be in the 1980s? It will either be stirring the imagination of the medical world or be another “false alarm in the world of hope.” At this time, a prestigious and successful U.S. pharmaceutical company is reviewing carnitine for possible licensing. The company has decided unequivocally that carnitine is an exciting therapeutic prospect with substantial market potential. The major stumbling block, however, is the patent. The company desires exclusive marketing rights for at least 5 years before it can justify the financial investment required to develop carnitine. They believe it may be relatively easy for a competitor to “get around” the present use patents, permitting the competitor to sell carnitine at very low cost. A further difficulty arose when a recent court decision ruled that use patents cannot be commercialized on an exclusive basis. So, if a U.S. company spends millions to develop carnitine, it must offer a license to other companies upon request. To be sure, the other companies must pay royalties to the company with the use patent, but the rate of return on the investment would be substantially less than if the company could sell carnitine exclusively. These problems have not been resolved.
The message of the carnitine story, however, is not dependent on the fate of this drug. The message is more universal: We have quietly and effectively eliminated the environment necessary for creativity in medicine. Few physicians discover new drugs or active pharmaceutical substances these days, simply because there is no support from any direction. The executive and legislative branches of the Federal government have been and are callous to the suffering of the sick.
One single act could revolutionize the therapeutic potential of medicine: let Congress pass legislation that would create strong patents for natural substances. In a perverse way, Congress has decreed that artificial, synthesized molecules can be protected by strong patents. Nature certainly has a more impressive track record than artificial substances in the battle against disease. Plants, animals, and humans constantly hold off the onslaught of fatal and degenerative disease. Something in us prevents bacteria from invading the bloodstream, arthritis from attacking our joints, and cancer from attacking us at any age. Natural substances in the brain combat depression, create genius, and permit happiness. If economic incentive is essential to bring forth natural therapeutic agents, then Congress should act to structure the appropriate system. Any movement which pushes for national health insurance and ignores natural substances, is irresponsible and immoral.
Where do we go from here? First and foremost, a spirit of innovation is sorely needed. In medicine, the clinical evaluation of ideas is the essential ingredient for advances in therapy. Regulatory, legal, moral, economic, and attitudinal barriers create formidable obstacles to clinical research. If they didn’t exist, carnitine would have been evaluated over a decade ago. There is no reason I couldn’t have gone to a medical school, pleaded my case, found an interested investigator, and proceeded with the clinical trials. The presence of regulations or human research committees does not increase the morality of clinical research. In fact, their inhibiting effect on clinical research is far more immoral than moral.
From where will the renewed spirit of innovation arise? Academic medicine, the health industry, and government are too inflexible and political. The truth is hard to find there, and optimism is rare. As structured today, these institutions do not truly represent the pioneering spirit of medicine. They have forgotten the innovator.
Who, then, will lead the way? There is only one type of medical institution that has the muscle and clout to battle our present health system with sufficient strength. These are the medical foundations. They are still relatively flexible. They could truly represent the patient by emphasizing the importance of freeing innovators to test their ideas. With a little help from the media, this is possible. After all, patients don’t want national health insurance to take care of them after their strokes if they can support clinical research to prevent strokes. Isn’t it time that someone asks the patient, “What do you want?” Isn’t it time that patients represent themselves at Congressional hearings on health? And isn’t it appropriate that foundations take the position of patient advocate?
The carnitine story is a case history involving practically all aspects of the anti-innovative forces in our country. Perhaps it will spark the foundations to come forth and fight the battle for the innovator.
As a physician, I was drafted at a late age during the Vietnam War. Fortunately, I landed a position as a clinical phammacologist at the Walter Reed Army Institute of Research. There I met the then Major James Vick, a well-known cardiovascular pharmacologist who specialized in toxins and shock. After I commiserated with the Major about carnitine, he enthusiastically offered to perform the first preclinical evaluation on isolated ischemic dog hearts. Little did he know that he would continue to perform carnitine studies over the next decade, sufficient time for him to earn the rank of colonel. Without Jim Vick, the carnitine story would have been even more frustrating and more prolonged. He encouraged me when I needed it with, “Steve, let’s do it,” and he cautioned me when it was necessary with, “Steve, each dog costs one hundred dollars. Are you sure you want to do it?” Frequently, he performed the studies at night, working in various laboratories to evaluate carnitine. If the future brings substantial benefit to the sick from carnitine, much of the credit belongs to Jim Vick.
For different reasons, I’d like to thank Mr. Isaac McGraw, Mr. Lyn Fordham, Dr. Laszlo Darko, Dr. Joseph DiPalma, Dr. Silvio Garattini and his associates at the Mario Negri Institute, Dr. Louis Lasagna, and Dr. Rolf Madaus for helping the cause at critical times, and my associate, Dr. Monroe Klein whose tireless efforts are speeding on the arrival of carnitine.
Finally, my thanks to Dr. Sheldon Gilgore, whose enthusiasm and help in the beginning of the carnitine story were critical in maintaining my bias.
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