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Exploratory Open Label, Randomized Study of Acetyl- and Propionylcarnitine in Chronic Fatigue Syndrome

From the Research Center Amsterdam, Amsterdam, Netherlands.

Address correspondence and reprint requests to Ruud Vermeulen, MD, PhD, CFS Research Center Amsterdam, Waalstraat 25, Amsterdam, 1078 BR, Netherlands. E-mail: info{at}cfscentrumamsterdam.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVES: We compared the effects of acetylcarnitine, propionylcarnitine and both compounds on the symptoms of chronic fatigue syndrome (CFS).

METHODS: In an open, randomized fashion we compared 2 g/d acetyl-L-carnitine, 2 g/d propionyl-L-carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks. Effects were rated by clinical global impression of change. Secondary endpoints were the Multidimensional Fatigue Inventory, McGill Pain Questionnaire, and the Stroop attention concentration test. Scores were assessed 8 weeks before treatment; at randomization; after 8, 16, and 24 weeks of treatment; and 2 weeks later.

RESULTS: Clinical global impression of change after treatment showed considerable improvement in 59% of the patients in the acetylcarnitine group and 63% in the propionylcarnitine group, but less in the acetylcarnitine plus propionylcarnitine group (37%). Acetylcarnitine significantly improved mental fatigue (p = .015) and propionylcarnitine improved general fatigue (p = .004). Attention concentration improved in all groups, whereas pain complaints did not decrease in any group. Two weeks after treatment, worsening of fatigue was experienced by 52%, 50%, and 37% in the acetylcarnitine, propionylcarnitine, and combined group, respectively. In the acetylcarnitine group, but not in the other groups, the changes in plasma carnitine levels correlated with clinical improvement.

CONCLUSIONS: Acetylcarnitine and propionylcarnitine showed beneficial effect on fatigue and attention concentration. Less improvement was found by the combined treatment. Acetylcarnitine had main effect on mental fatigue and propionylcarnitine on general fatigue.

Key Words: acetylcarnitine, • attention concentration, • carnitine, • chronic fatigue syndrome, • propionylcarnitine.

Abbreviations: ALC = acetyl-L-carnitine;; CFS = chronic fatigue syndrome;; CGI = clinical global impression of change;; CDC = Centers for Disease Control and Prevention;; DSM-IV = Diagnostic and Statistical Manual;; MFI-20 = multidimensional fatigue inventory;; MPQ-DLV = McGill Pain Questionnaire–Dutch language version;; OCTN2 = organic cation transporter/carnitine transporter Na⁺-stimulated;; PLC = propionyl-L-carnitine;; RBE4 = rat brain endothelial cells;; VAS = visual analogue scale.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
Estimations of the prevalence of chronic fatigue syndrome (CFS) range from 1 to 4 (1,2). Although the cause of CFS is not known, sets of criteria for diagnosis of the condition have been published. The most widely accepted criteria were formulated in the consensus meeting supervised by the Centers for Disease Control and Prevention (CDC) (3). Patients with CFS are defined by the presence of clinically evaluated, unexplained persistent chronic fatigue of new or definite onset (not lifelong) resulting in substantial reduction in previous levels of activities, and the occurrence of 4 or more of the following symptoms (all of which must have persisted for 6 months and must not have predated the fatigue): self-reported severe impairment in short-term memory or concentration, sore throat, tender lymph nodes, muscle pain, multijoint pain without swelling or redness, headache of a new type, unrefreshing sleep, and postexertional malaise lasting more than 24 hours. Exclusions include a clear underlying organic cause, substance misuse, and severe psychiatric disorder such as psychotic depression. Less severe psychiatric disorders such as major depression without Diagnostic and Statistical Manual (DSM)-IV-defined melancholic features or anxiety disorders are not exclusionary diagnoses and are frequently comorbid with CFS (4).

Kuratsune et al. (5) and Plioplys and Plioplys (6) reported a decrease in plasma acylcarnitine in CFS, but this was not confirmed by others (7–9). The first report on carnitine treatment in CFS was by Grau et al. (10), who found no effect. Plioplys and Plioplys (11) reported significant improvement of CFS symptoms after 2 months of 3 g daily orally administered L-carnitine.

In a preliminary open label study, we treated 150 CFS patients with 1 g oral L-carnitine bid. After 6 months, 104 patients (69%) reported marked improvement by clinical global impression of change (CGI) ["I feel (very) much better"]. Another 18 CFS patients were included in a randomized double-blind study. Six were treated with oral acetyl-L-carnitine 1 g/d plus L-carnitine 1 g/d (low dose), 6 received twice the dosage (high dose), and 6 received placebos. After 6 months, marked improvement was reported by 4 patients in the low dosage group, by none in the high dosage group, and by 1 in the placebo group (unpublished results).

Carnitine is essential for the mitochondrial oxidation of long-chain fatty acids (12), because it acts as a carrier of acyl groups across the inner mitochondrial membrane to the matrix for ß-oxidation. Later, many more functions were detected in detoxification of acyl-CoA and acylcarnitine export from the cell, increasing free CoA/acyl-CoA in the cell affecting lipid, protein, and carbohydrate metabolism [review (13)], membrane synthesis and repair (14), and ac(et)ylation of amino acids, histones, and proteins. The latter process is involved in posttranslational modification, membrane binding, and G-protein signaling. Carnitine promoted perfusion in ischemia (15), decreased oxidative stress (16,17), and attenuated damaging effects of mitochondrial inhibitors and uncoupler in neurons (18). Mitochondria were not the only organelles participating in the actions of the carnitine system; also peroxisomes, endo- and sarcoplasmic reticulum, and nuclear membrane metabolized carnitine (19). Moreover, every human cell (including the erythrocyte) contains carnitine palmitoyltransferase activity, and carnitine and acylcarnitines were detected in every cell compartment and body fluid (13). Many biochemical, pharmacological, and clinical studies have investigated the action of carnitine and its esters acetylcarnitine and propionylcarnitine. Acetylcarnitine is a universal mitochondrial energy source and acetyl donor. It promoted energy metabolism and neurotransmission in the aged or neurotoxin-treated or ischemic reperfused rodent brain [reviews (18,20)]. Promising results were obtained in human degenerative brain diseases [review (21)]. Propionylcarnitine is also an energy source, stimulated the Krebs cycle as a precursor of succinyl-CoA, decreased oxidative stress in various systems, and improved cardiac dysfunction in rodent models (20,23). It was found to be effective in human cardiovascular disorders [reviews (24,25)]. Acetyl- and propionylcarnitine appeared generally somewhat more effective than L-carnitine.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
We compared the effect of acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) on complaints of patients with CFS. We chose to conduct an open exploratory study with a discussion with the participants about the experienced change in their clinical condition, supported by objective questionnaires. The sample size was based on the results of the 2 preliminary studies mentioned above, indicating improvement in 50% of the patients in the low dose groups and less than 20% in the high dosage group. The sample size was not based on differences between the ALC and the PLC groups because data were not available. The present trial included 90 patients with CFS according to the CDC criteria, in an open randomized study. Patients were recruited from the polyclinic at the CFS Research Centre Amsterdam. Excluded were patients with an evident underlying organic cause, substance misuse, and severe psychiatric disorder such as psychotic depression. Presence of exclusion criteria according to the CDC (3,4) was revealed by structured interview, physical examination, and extensive laboratory tests. Before entry into the study, the nature of the study was explained to the patients and written consent was obtained. An independent ethics committee approved the study. The trial was conducted in accordance with the Declaration of Helsinki (1996 revision) and under the principals of good clinical practice, as laid out in the International Conference on Harmonisation document Good Clinical Practice Consolidated Guideline. All analyses were conducted on an intent-to-treat basis, with the last recorded value on each outcome measure being carried forward to the end of the trial, unless stated otherwise. Randomization was performed after opening of sealed envelopes with the randomization codes and by blocks of 6 patients, stratified for gender, and assigned the patients to an ALC group, a PLC group, and an ALC+PLC group. After randomization, patients received 2 g acetyl-L-carnitine per day in the ALC group, 2 g propionyl-L-carnitine in the PLC group, and 2 g ACL plus 2 g PLC in the ALC+PLC group. The medication was taken after breakfast and dinner for 24 weeks. The dropouts were analyzed during the whole trial, and their data were included in the results.

The trial profile is presented in Figure 1. Assessed for eligibility were 114 patients, and 90 were enrolled in the study. Table 1 shows the gender distribution (78% females), the average age (37–42 years), the duration of CFS (median 3 years or more), and the plasma carnitine levels at randomization, that were (about) the same in the ALC, the PLC, and the ALC+PLC group. The plasma carnitine and carnitine esters levels showed no abnormalities and were similar to those in controls (8).

View larger version (30K): [in this window] [in a new window]   Figure 1. Trial profile

Clinical Assessment
At screening patients’ complaints, cognitive performance and pain were assessed. This was repeated after a no-treatment period of 8 weeks, and then the patients were randomly distributed in 3 groups and treated for 24 weeks. During treatment, patients were reassessed at 8, 16, and 24 weeks. Patients reported after 2 weeks of no-treatment whether the withdrawal of medication had influenced their condition compared with 2 weeks earlier. The primary endpoint of the study was the CGI (26). CFS is a condition without objective criteria. Accordingly, in this study of CFS, the CGI was rated according to the subjective experience of the patient, who had to answer the question: Do you experience a change in your condition compared with the time of randomization? The CGI was rated on a 5-point scale, ranging from -3 very much worse, to +3 very much better. Secondary endpoints were the fatigue axes of the Multidimensional Fatigue Inventory (MFI-20) (27), the Stroop test for attention concentration (28), and the McGill Pain Questionnaire-Dutch Language Version (MPQ-DLV) for pain (29). The MFI-20 consists of 20 questions, the general, physical, and mental fatigue axes were used in the study. The score on each axis is 5 to 20 points, indicating no fatigue to extreme fatigue. The Stroop test estimates attention concentration. The result of the reading time of the third card minus that of the second card of the Stroop test is shown because in the preliminary studies (mentioned above) this gave the best results to differentiate patients from controls. The score given is the time needed to read aloud the names of 100 words of colors printed in another color minus the time needed to read aloud the colors of 100 stripes. The Stroop test can be used more than 1 time without affecting the interference score by a practice or learning effect (30). The McGill Pain Questionnaire-Dutch Language Version (MPQ-DLV) was used for the assessment of pain. The result of the visual analogue scale (VAS) pain score is expressed as a distance of 0 to 100 mm, indicating no pain to extreme pain. A trained psychologist administered all questionnaires and tests.

Biochemical Procedures
Blood was sampled by venipuncture in heparin tubes at randomization and after the 24-week treatment period, for the assay of free carnitine and carnitine esters in plasma, using tandem mass spectrometry as described by Vreken et al. (31).

Statistical Analysis
Data are expressed as mean and SD, unless indicated otherwise. Statistical analysis was done with SPSS 11.0. Correlations were calculated by Pearson’s correlation test for continuous data with a normal distribution. Data with a not-normal distribution were tested with Spearman rank correlation test. Changes of scores during therapy were tested by Friedman’s test for multiple related variables. Significant levels were assumed at p < .05. Bonferroni correction was applied for multiple observations.

Role of the Funding Source
The funding source had no role in the decision to publish the data and in the writing of the paper.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
Table 2 summarizes the CGIs after 8 weeks of no treatment and after 8, 16, and 24 weeks of treatment. Improvement was reported after 24 weeks of treatment by 59% of the ALC group, 63% of the PLC group, and 37% of the ALC+PLC group, whereas 10% in the ALC group, 3% in the PLC group, and 16% in the ALC+PLC group felt worse.

Table 3 summarizes the general fatigue, physical fatigue, and mental fatigue scores. Significant improvement of general fatigue score was found in the PLC (p = .004) and in the ALC+PLC group (p = .000), and that of mental fatigue in the ALC group (p = .015). The physical fatigue score was not significantly improved in the PLC group (p = .069).

The levels of plasma L-carnitine increased significantly in all groups of patients, but somewhat less in the responders. Surprisingly, carnitine levels in the group receiving ALC plus PLC became not considerably higher than in the other 2 groups. The levels of the carnitine esters increased in all groups, but remained low compared with L-carnitine (Table 5). The increase of carnitine levels in women was not different from that in the male participants.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
The first aim of the study was to compare the different influences of acetylcarnitine and propionylcarnitine on symptoms of CFS. The second goal was to obtain an indication of the percentage of responders. Therefore, the study was designed as an observation period of 8 weeks, followed by a randomized trial and an observation period of 2 weeks.

In the first observation period the scores for fatigue, concentration, and pain of the patients proved to be stable. The medication was well accepted by the patients, with a dropout number of 8 because of side effects. The nature of the side effects—overstimulation and sleeplessness—is different from those reported in most other studies, describing trimethylamine formation or diarrhea in a few patients.

In advance, we had expected that ALC would have most effect on attention concentration, PLC on physical fatigue, and ALC+PLC on both. The CGI improved in the ALC and the PLC group, but not significantly in the ALC+PLC group, likely because of the higher total carnitine ester dose and indicating an inversed U-form dose–response curve. An indication for the same effect was found in the preliminary double-blind pilot study. The effect of ALC on mental fatigue and attention concentration was significant. The PLC group showed most improvement in general and physical fatigue and slightly less in attention concentration. The ALC+PLC group improved very well on general fatigue and also, but not significantly, on physical and mental fatigue. The pain score was not influenced in a significant way by any medication.

The CGI as an overall impression correlated significantly with the change of the 3 separate fatigue scores, thus validating the concept (not shown).

In the present study, all patients had normal plasma free carnitine levels, and a normal spectrum of the acylcarnitine species, excluding primary and secondary carnitine deficiency (Table 1).

In the second observation period, 50% of patients deteriorated in the ALC and PLC groups. For most the relapse was hardly acceptable, because they had adapted their activity to the improvement. The improved patients in the ALC+PLC group (37%) all deteriorated in the second observation period.

The different effects of acetylcarnitine and propionylcarnitine could be explained by a different transport of the esters from plasma to the tissues and the brain. If so, the observation that the concentration of carnitine in the plasma in the ALC group increased more in patients with less therapeutic effect, indicates lower transport. It is conceivable that ALC and PLC are not transported as such, because the plasma ALC and PLC levels were relatively low and showed no correlation with improvement. The precise mode of action of the carnitine esters in alleviating the CFS symptoms is not clear. In this study, acetylcarnitine apparently had a more "central" action and propionylcarnitine a more "peripheral" action, which is in line with other human studies. It is generally thought that acetylcarnitine can easily pass the blood–brain barrier, and that propionylcarnitine preferentially enters the heart. The fate of double-labeled acetylcarnitine has been studied by Kuratsune et al. (32). They showed that only the acetyl moiety is rapidly taken up by the brain, leaving the carnitine moiety in the circulation. This was in line with older studies [reviewed in (13)] establishing that carnitine import in the brain is a slow process with low affinity. Recently, however, with immortalized RBE4 cells, an in vitro model of the blood–brain barrier, it was shown that these cells expressed the high-affinity carnitine transporter OCTN2, and transported carnitine, acetylcarnitine, and propionylcarnitine (33). When this is the case, a preferential uptake of acetylcarnitine by brain and a preferential uptake of propionylcarnitine by heart are less likely, because OCTN2 is also present in muscle and several other cells. Perhaps another messenger contributes to, or is involved in, the action of the carnitine esters, such as purines (34) or cortisol.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
This study indicates that both ALC and PLC are successful in the treatment of symptoms of CFS in a major subset of CFS patients. The fact that the pattern of improvement by acetylcarnitine, propionylcarnitine, and their combination was not identical suggests that differences in transport and/or metabolism are involved in their action.

Conclusive evidence for the effects of carnitine esters on CFS will have to await a double blind, placebo-controlled, randomized trial.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
Sigma-Tau Ethifarma, Assen, The Netherlands, sponsored the study and provided the study medication.

We thank Otto J. Bauermann (Sigma-Tau Ethifarma) for his cooperation and Professor J. F. Koster for reading of the manuscript.

Received for publication January 22, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 

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