Stephen L. DeFelice M.D.
March 13, 2003
During the Vietnam war, Major James Vick, a cardiovascular pharmacologist, and I conducted a series of laboratory studies at the Walter Reed Army Institute of Research (WRAIR) which demonstrated that carnitine dramatically prevented or reversed myocardial ischemia, a lack of oxygen to the heart.
Following these studies, we decided to conduct other laboratory studies on whether carnitine could block lethal doses of certain toxins. We evaluated primarily cardiovascular effects and survival. Some of these studies were conducted at other facilities.
Frankly speaking, our hopes of success were not that high, but we thought that, given carnitine’s effect on protecting the heart against a lack of oxygen, it was worth a try. We also had read that other investigators had demonstrated that carnitine protects against lethal doses of diphtheria toxin in animals.
Then came the unexpected surprise. Carnitine, when given as treatment, after the toxicity process was in full swing, reversed the toxicity of the lethal doses of E.coli bacterial toxin, Russell’s Viper venom, palytoxin and adriamycin in almost all of the animals and other laboratory experimental models such as isolated hearts.
Excited by these findings, I contacted a number of pharmaceutical companies about carnitine’s potential for the treatment of sepsis and septic shock which is increasingly common in hospitals. I ran into a stone wall mainly because of the absence of a strong carnitine patent. Our colleagues in the government expressed interest, but the opportunity somehow fell through the cracks. It was probably due to the fact that, because of urgency of the Vietnam war, almost everybody in those days was trying mightily to find therapies to counter malaria infection and radiation damage. The bioterrorism threat was not yet a significant national issue.
I had no choice but to set aside this project, but Major Vick continued to conduct other laboratory studies with carnitine with exciting results.
I then decided to pursue carnitine for the medical condition of myocardial ischemia where the animal data continued to be highly promising. After communicating with approximately thirty U.S. and international pharmaceutical companies, I met Dr. Claudio Cavazza, the proprietor of the privately held, research-oriented Italian pharmaceutical company, Sigma-tau S.p.A.
Based on biochemical as well as pharmacological data, he became convinced of carnitine’s broad medical potential, and invested, and has continued to invest, substantial amounts of money in basic and clinical research including the development of related molecules such as l-acetylcarnitine and proprionylcarnitine.
Time passed and we paused different paths for awhile. When, however, the anthrax scare burst on the national scene and the real possibility that bioterrorism agents which cause septic shock could be used as weapons of mass destruction, I became somewhat alarmed. I then called Dr. Cavazza to discuss this situation and was very happy with what I heard.
In the past, some preliminary laboratory studies in septic shock with l-acetylcarnitine were conducted with promising results. For example, one study reported that l-acetylcarnitine could significantly block the lethal dose of the bacterial endotoxin substance, LPS.
In addition, two preliminary clinical studies were done in patients with septic shock with encouraging results.
In the first study, l-acetylcarnitine was administered intravenously and found to improve the metabolism of body fuel substrates such as fatty acids and branched-chain amino acids. In septic shock patients, the mitochondria, the energy producing parts of the cell, are compromised. Also, there is an increase in blood coagulation, which reduces the blood supply to body tissues and, therefore, much needed oxygen to the cells. This further compromises mitochondrial function leading to a decrease in the cells’ metabolic capacity to generate fuel not only to maintain normal functioning cells but also to keep them alive. Despite the seriously compromised mitochondria and significant decreased in energy output, l-acetylcarnitine managed to increase cellular production of energy.1
A preliminary double-blind clinical study was conducted in patients with septic shock. Both during and after the infusion of l-acetylcarnitine both systolic and diastolic blood pressure were significantly elevated. Also, the clinical investigations reported and improvement in blood oxygenation.2
Now let’s switch gears to some interesting recent findings regarding the central nervous system, l-acetylcarnitine and septic shock patients.
Because of promising scientific data, Dr. Cavazza decided to develop acetyl-carnitine for medical conditions that involve the central nervous system, or brain, as well as the peripheral nervous system. In addition to having the cardioprotective effects of carnitine, l-acetylcarnitine offers additional benefits by protecting nerve cells when they are seriously challenged.
Drs. Wesley Ely and other experts in shock management at the Vanderbilt University Medical Center found that delirium, which is common in septic shock, is an indicator or prognosticator of certain clinical outcomes or how well or poorly a patient does.3-4
It is not commonly appreciated that septic shock patients who managed to survive the life-threatening crisis have serious debilitating clinical sequelae, including those involving the central nervous system. They found that the degree of these debilitating central nervous system effects were proportional to the severity and duration of the delirium. Also, the more severe the delirium, the lower the survival rate and the duration in the hospital is significantly longer.
These data suggest that there is a real possibility that the brain may play a major role in septic shock.
There are a number of laboratory studies that report that l-acetylcarnitine is an active molecule in the brain. For example, a study was conducted in dogs to determine whether carnitine and l-acetylcarnitine protected the dog brain after it was deprived of oxygen by inducing cardiac arrest. It was found that l-acetylcarnitine significantly reversed the neurologic deleterious effects of oxygen deprival, while carnitine did not. The investigators conclude that l-acetylcarnitine works by restoring the brain’s normal aerobic or oxygen-based metabolism, normalizing the production of ATP, or cell energy.5
Similar brain protecting properties of l-acetylcaritine against oxygen deprivation in rats has also been reported.
The brain effects of l-acetylcarnitine have not yet been studied in septic shock animal models or patients. We do know, however, that it crosses the blood-brain barrier in humans. It stimulates the production of plasma cortisol and endorphins and increases cerebral blood flow to certain parts of the brain. It has also been reported to benefit patients with certain diseases of the nervous system.
L-acetylcarnitine’s combined cardiovascular and central nervous system properties offer promise to septic shock patients. I have consulted with a group of experts who, after evaluating all the promising pieces of evidence, agreed that it is worthy of a clinical trial in such patients.
There are approximately 750,000 cases of severe sepsis a year, with about a thirty-three percent mortality rate. Septic shock now kills more patients per year than breast, colon, pancreatic and prostate cancers combined!
It is important to note that bioterrorism toxic agents cause septic shock or damage the brain or do both. In my opinion, the possibility that l-acetylcarnitine may counter some of these toxic effects should be pursued either alone or in combination with other promising agents.
References:
Gasparetto A., Corbucci G.G., DeBlasi R.A., Antonelli M., Baqiella E., D’eddio
S., Trevisani C.: Influence of acetyl-carnitine infusion on haemodynamic parameters and survival of circulatory-shock patients. INT.J. CLIN. PHARM.RESX1(2)83-92 (1991)
Nanni G., Pittiruti M., Giovannini I., Boldrini G., Ronconi P., Castagneto M.: Plasma carnitine levels and urinary excretion during sepsis.
JPEN9: 483-490, 1985
Ely, E.W., Jackson, J., Shinitani, G.S., May, L., Truman, B., Dittus, B., Gautam. S., Bernard, G., Speroff, T., Hart R. Long-term neuropsychological deficits following delirium in mechanically ventilated ICU patients. Am. J. Respir. Crit. Care Med. 165(8):A30, 2002. (now in press at Crit Care Medicine after peer review)
Ely, E.W., Shintani, A., Bernanrd, G., Jackson., J., Gordon, S., May, L., Truman, B., Gautam, S., Inouye, S., Dittus, B., Speroff, T. Delirium in the ICU is associated with prolonged length of stay in the hospital and higher mortality. Am J. Respir. Crit Care Med. 165(8):A23, 2002. (now under review at NEJM)
Rosenthal, R.E., Williams, R., Wells W., Fiskum, G., Post-ischemic administration of acetyl-l-carnitine (ALCAR) prevents neurological injury following prolonged cardiac arrest in dogs, Abstract No. DV9, Pharm. Of Cerebral Ischemia ’92, Marburg, Germany (1992).