Zithro works to knock out borrelia, not as an immune modulator

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Azithromycin in Chronic Fatigue Syndrome (CFS)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

an analysis of clinical data

Authors: Ruud CW Vermeulen and Hans R Scholte

Journal of Translational Medicine 2006, 4:34

doi:10.1186/1479-5876-4-34

Published 15 August 2006

Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of

clinical data

Ruud C.W. Vermeulen*1 and Hans R. Scholte2

Address: 1CFS and Pain Research Center Amsterdam, Waalstraat 25-31,

1078 BR Amsterdam, The Netherlands, 2Department of Biochemistry,

Erasmus MC-University Medical Center Rotterdam, Rotterdam, The

Netherlands.

E-mail: Ruud CW Vermeulen* - rv@...;

Hans R Scholte h.scholte@....

* Corresponding author

Abstract

Background: CFS is a clinical state with defined symptoms, but

undefined cause. The patients may show a chronic state of immune

activation and treatment with an antibiotic in this subgroup has been

suggested.

Methods:

In a retrospective study, the response of CFS patients to

azithromycin, an antibiotic and immunomodulating drug, has been

scored from the patients records and compared with clinical and

laboratory data. Azithromycin was not the first choice therapy, but

offered when the effect of counseling and L-carnitine was considered

insufficient by the patient and the clinician.

Results:

Of the 99 patients investigated, 58 reported a decrease in the

symptoms by the use of azithromycin. These responding patients had

lower levels of plasma acetylcarnitine.

Conclusion:

The efficacy of azithromycin in the responsive patients could be

explained by the modulating effect on a chronic primed state of the

immune cells of the brain, or the activated peripheral immune system.

Their lower acetylcarnitine levels may reflect a decreased

antioxidant defense and/or an increased consumption of

acetylcarnitine caused by oxidative stress.

Background

In 1994 Fukuda et al. [1] defined CFS as a chronic persistent fatigue

that is present for over 6 months, is not caused by activity nor

alleviated by rest and accompanied with at least 4 other

symptoms: cognitive impairment, pain in joints, muscles or head,

unrefreshing sleep, soar throat, tender lymph nodes and

postexertional malaise with slow recovery. Nevertheless, CFS remained

subject to debate and even the mere existence of the syndrome was

still questioned by some. The presentation of the results of

quantitative morphology of the brain in CFS patients by Okada et al

[2], later confirmed by De Lange et al [3] may change this opinion.

The loss of grey matter in the brain, especially in Brodmanns area

9, was related to physical impairment, but not to the duration of the

symptoms. Although other explanations were considered as well, this

may indicate the occurrence of a major trauma to the brain at the

start of the disease. This could also explain the low recovery rate

in adults, because repair in adult brain is limited [4].

The severity of the sickness, both the symptoms and the lowered

adaptation to physical stress, may fluctuate whenever infections and

stress come and go. The Th1 to Th2 cytokine shift in CFS patients

will make them more vulnerable to infections [5] and it has been

suggested that they have more often chronic infections [6-8]. The

predisposition for acquiring CFS may be genetically determined [9,

10], the occurrence is influenced by the severity of the immune

response [11]. The result is a chronic hyper-oxidative state of

sickness [12, 13], in the brain itself [14] that cannot be stopped

[15]. Preliminary evidence of a relation between post-infectious

fatigue and mitochondrial dysfunction indicates a complex response

involving acetylcarnitine [16].

The clinical presentation of the symptoms and chances for recovery

will depend on the balance between the irreversible loss of grey

cells and activation of the immune system.

According to De Meirleir et al, the presence of RNase-L and elastase

may offer an indication for this balance [17-19].

Several treatment protocols to counteract the immune activation in

CFS were presented [18, 20, 21], but the results were never validated

in a double blind study. Such proof is required as a rationale for

treatment and provides a basis to understand the pathophysiology of

the disease. Comparing the outcome of clinical treatment protocols

might add to our knowledge of CFS and its treatment until double

blind studies are available [22] .

Azithromycin is an antibiotic with immunomodulatory effects [23-25].

This antibiotic has been successfully used during periods of six

months of more in other chronic diseases [26-28].

The side-effects are known for long term use and mainly limited to

gastro-intestinal cramps. The chances for resistance limit its use to

individual patients under close supervision [28]. The drug is

relatively inexpensive and extensive laboratory tests for side

effects are not necessary. The result of a study in 10 CFS patients

during 1 to 2 months was positive [26]. We studied the medical

records of CFS patients for clinical and laboratory data related to

the outcome of the treatment with azithromycin.

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March 13, 2003

Bioterrorism: The Potential Role of L-Acetylcarnitine in the

Treatment of Sepsis and Septic Shock

L. DeFelice M.D.

During the Vietnam war, Major Vick, a cardiovascular

pharmacologist, and I conducted a series of laboratory studies at the

Walter 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.

ly 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, '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., , 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., ., 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., , 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).

1: Infection. 1993 Mar-Apr;21(2):83-8. Related Articles, Links

Azithromycin versus doxycycline for treatment of erythema migrans:

clinical and microbiological findings.

Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb

M.

Department of Infectious Diseases, University Medical Center,

Ljubljana, Slovenia.

The effectiveness of azithromycin and doxycycline in the

treatment of erythema migrans was compared in a prospective

randomized trial. One hundred seven adult patients with typical

erythema migrans, examined in the Lyme Borreliosis Outpatients'

Clinic, University Department of Infectious Diseases in Ljubljana,

were included in the study. Fifty-five patients received azithromycin

(500 mg twice daily for the first day, followed by 500 mg once daily

for four days) and 52 patients received doxycycline (100 mg twice

daily for 14 days). The mean duration of skin lesions after the

beginning of treatment was 7.5 +/- 5.9 days (median value 5, range 2-

28

days) in the azithromycin group and 11.4 +/- 7.8 days (median value

9, range

2 days--8 weeks) in the doxycycline group (p < 0.05). Borrelia

burgdorferi was isolated from erythema migrans in 28 patients before

therapy: in 13 out of 52 in the doxycycline group and in 15 out of 55

in the azithromycin group. Three months after therapy, the culture

was positive in four out of

13 patients treated with doxycycline and in one of the 15 patients

who received azithromycin. A biopsy was repeated in all the patients

with a positive isolation from the first skin specimen. During the

first 12 months'

follow-up, three patients treated with doxycycline but none in the

azithromycin group developed major manifestations of Lyme

borreliosis, while

15 doxycycline recipients and 10 azithromycin recipients developed

minor consecutive manifestations.

Publication Types:

* Clinical Trial

* Randomized Controlled Trial

PMID: 8387966 [PubMed - indexed for MEDLINE]