Bioterrorism: The Potential Role of L-Acetylcarnitine in the Treatment of Sepsis and Septic Shock
Stephen L. DeFelice M.D.
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
I had no choice but to set aside this project, but Major Vick
continued to conduct other laboratory studies with carnitine with
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
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
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
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
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
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).