Altern Med Rev. 1998 Oct.
L-Carnitine: therapeutic applications of a conditionally-essential amino acid.
Kelly GS.
[ PubMed ] [ Free full text ]

Abstract: A trimethylated amino acid roughly similar in structure to choline, carnitine is a cofactor required for transformation of free long-chain fatty acids into acylcarnitines, and for their subsequent transport into the mitochondrial matrix, where they undergo beta-oxidation for cellular energy production. Mitochondrial fatty acid oxidation is the primary fuel source in heart and skeletal muscle, pointing to the relative importance of this nutrient for proper function in these tissues. Although L-carnitine deficiency is an infrequent problem in a healthy, well-nourished population consuming adequate protein, many individuals within the population appear to be somewhere along a continuum, characterized by mild deficiency at one extreme, and tissue pathology at the other. Conditions which seem to benefit from exogenous supplementation of L-carnitine include anorexia, chronic fatigue, coronary vascular disease, diphtheria, hypoglycemia, male infertility, muscular myopathies, and Rett syndrome. In addition, preterm infants, dialysis patients, and HIV+ individuals seem to be prone to a deficiency of L-carnitine, and benefit from supplementation. Although available data on L-carnitine as an ergogenic aid is not compelling, under some experimental conditions pretreatment has favored aerobic processes and resulted in improved endurance performance.

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Selected excerpts from the full text article:

Introduction

Although L-carnitine was originally discovered in 1905, its crucial role in metabolism was not elucidated until 1955, and primary L-carnitine deficiency was not described until 1972. The most significant source of L-carnitine in human nutrition is meat, although humans are also capable of synthesizing L-carnitine from dietary amino acids. It has generally been assumed that a well-balanced diet contains both a significant amount of carnitine, and all of the essential amino acids and micronutrients needed for carnitine biosynthesis; however, increasingly investigators have identified conditions and individuals for which L-carnitine appears to be a conditionally-essential nutrient. Thus, although L-carnitine deficiency is an infrequent problem in a healthy, well-nourished population consuming adequate protein, many individuals within the population appear to be somewhere along a continuum characterized by mild deficiency at one extreme and tissue pathology at the other.

Biochemistry

A trimethylated amino acid similar in structure to choline, carnitine (see Figure 1) is a cofactor required for transformation of free long-chain fatty acids into acylcarnitines, and for their subsequent transport into the mitochondrial matrix, where they undergo betaoxidation for cellular energy production. Mitochondrial fatty acid oxidation is the primary fuel source in heart and skeletal muscle, pointing to the relative importance of this nutrient for proper function in these tissues.

Carnitine synthesis begins with methylation of the amino acid L-lysine by Sadenosylmethionine (SAM). Methionine, magnesium, ascorbic acid, iron, P5P, and niacin, along with the cofactors responsible for regenerating SAM from homocysteine (5-methyltetrahydrofolate, methylcobalamin, and betaine) are all required for endogenous carnitine synthesis (see Figure 2).

In order to form L-carnitine from lysine, three consecutive methylation reactions are required, with SAM acting as the methyl donor, resulting in the formation of trimethyllysine. Trimethyllysine is enzymatically transformed into hydroxytrimethyllysine in a reaction requiring alphaketoglutarate, oxygen, ascorbic acid and iron. The next step in the endogenous synthesis of L-carnitine requires pyridoxal 5'-phosphate (vitamin B6) and results in the formation of trimethylaminobutyraldehyde. Trimethylaminobutyrate (or gammabutyrobetaine) is then formed in a reaction requiring NADH (vitamin B3 dependent). The gamma-butyrobetaine is finally hydroxylated into carnitine in a reaction which again requires alpha-ketoglutarate, oxygen, ascorbic acid and iron.

A pivotal enzyme in carnitine synthesis, betaine aldehyde dehydrogenase is the same enzyme responsible for synthesis of betaine from choline. Two recent studies suggest this enzyme has a preference for the cholinebetaine conversion, since choline supplementation appeared to decrease carnitine synthesis.1,2

Pharmacokinetics

The pharmacokinetic properties of an orally administered dose of L-carnitine have not been unequivocally described in the literature, and might have considerable variability depending upon the relative carnitine stores of an individual. Evidence indicates L-carnitine is absorbed in the intestine by a combination of active transport and passive diffusion.3

There appears to be no significant advantage of supplementing an oral dose of L-carnitine in amounts greater than 2 g, since pharmacokinetic studies suggest mucosal absorption of carnitine is saturated at about a 2 g dose.4 Maximum blood concentrations are reached approximately 3.5 hours following an oral dose, with a half-life of about 15 hours. Elimination of carnitine occurs primarily through the kidneys.5

Although evidence suggests dietary carnitine is not totally absorbed and is in part degraded in the gastrointestinal tract of humans, there is some disagreement on the actual bioavailability of an oral dose. Rebouche and Chenard gave a radio-labeled dose of L-carnitine orally with a meal to subjects who had been adapted to a low-carnitine diet or a high-carnitine diet in order to determine the metabolic fate of dietary carnitine in humans. Their results suggested an oral bioavailability of 54 to 87 percent depending upon the dose of L-carnitine consumed.6 Bach et al also presented evidence suggesting relatively high absorption of L-carnitine. Following a 2 g oral dose of L-carnitine, they reported an increase in total blood carnitine levels of about 57 percent and in the free form of L-carnitine of about 81 percent.5

In contrast to these observations, several researchers have suggested much lower bioavailability. Sahajwalla et al indicated an absolute bioavailability of approximately 18 percent in healthy volunteers.7 Harper et al similarly reported a relatively low oral bioavailability. Following a 2 g dose they estimated bioavailability to be approximately 16 percent.4

Baker et al evaluated the changes in free and acylcarnitine activity in plasma, whole blood, red blood cells, and urine following oral doses of L-carnitine (a single dose of 500 mg or 2500 mg, or by ingestion of a daily dose of 2500 mg for 10 days). Increased levels of free carnitine were observed in the urine following all dosage regimens, while a single or consistent daily dose of 2500 mg of carnitine increased free and acylcarnitine in plasma, whole blood and urine to the greatest degrees. However, irrespective of dosage, these researchers observed no significant change in red blood cell carnitine levels, suggesting either a slow repletion of tissue stores of carnitine following an oral dose, or a low capability to transport carnitine into tissues under normal conditions.8 It is not known whether similar findings would be observed in conditions characterized by functional deficiency; however, based upon consistent clinical observations, it is likely some degree of tissue repletion occurs following an oral dose.

Deficiency

Although L-carnitine is supplied exogenously as a component of the diet and can also be synthesized endogenously, evidence suggests both primary and secondary deficiencies do occur. Carnitine deficiency can be acquired or a result of inborn errors of metabolism. Carnitine levels of vegetarians are reported to be below normal. Infants fed carnitine-free formulas are also in jeopardy of deficiency, since endogenous synthesis is not adequate to cover systemic needs during the first few days of the postnatal period. Primary carnitine deficiency, although rare, is characterized by low plasma, red blood cell, and tissue levels of carnitine, and generally presents with symptoms such as muscle fatigue, cramps, and myoglobinemia following exercise. Secondary carnitine deficiency is not as rare and is most commonly associated with dialysis, although intestinal resection, severe infections, and liver disease can also induce a secondary deficiency. Other symptoms of a chronic carnitine deficiency can include hypoglycemia, progressive myasthenia, hypotonia, or lethargy. Because of carnitine's role in fatty acid metabolism, elevated triglycerides as a lab finding might, among a variety of possibilities, be indicative of a relative deficiency of carnitine. Pathological manifestations of chronic deficiency include accumulation of neutral lipid within skeletal muscle, heart tissue and liver, a disruption of muscle fibers, and an accumulation of large aggregates of mitochondria within the skeletal and smooth muscle. Because of these changes, a deficiency can result in cardiomyopathy, congestive heart failure, encephalopathy, hepatomegaly, impaired growth and development in infants, and neuromuscular disorders.

Diet and Nutritional Interactions

It is assumed a diet adequate in protein will supply enough exogenous, and promote any additional endogenous, synthesis needed to supply an individual's requirements for L-carnitine. However, since L-carnitine is found primarily in animal proteins, with red meat regarded as the richest source, it is theoretically possible to consume a high protein diet consisting of beans, legumes, or egg whites and still promote a relative deficiency.

Since a vegetarian diet is very low in exogenous carnitine, and is potentially low in some of the substrates required for carnitine synthesis, there is some concern that following a strict vegetarian diet might produce a carnitine deficiency in some individuals. A case report in the literature seems to lend credence to this possibility. In this report, a 12-year-old consuming a vegetarian diet had recurrent episodes of vomiting, lethargy, and hypoglycemia dating back 11 years. Investigations revealed a systemic carnitine deficiency that, when corrected, promptly improved his condition.9

Results indicate the macronutrient composition of a diet, other than protein content, can influence carnitine metabolism. In seven healthy men receiving the same amount of dietary carnitine, plasma free carnitine rose significantly in individuals following a highfat, low-carbohydrate diet, while no change in carnitine level was observed in individuals on a high-carbohydrate, low-fat diet. Renal excretion of carnitine increased only on the higher fat diet as well. This evidence suggests a high-fat, low-carbohydrate diet might be capable of boosting endogenous synthesis of carnitine and its metabolites.10 Coupled with this observation is the clinical finding that some individuals consuming a high carbohydrate diet for prolonged periods of time present with vague symptoms of fatigue and hypoglycemia, symptoms which can be indicative of a relative carnitine deficiency. In these individuals it might be prudent to assess carnitine status.

Although medium-chain triglycerides (MCTs) have generally been assumed to be utilized as an energy substrate independently of carnitine, Rossle et al have shown the administration of MCTs does impact plasma concentrations of free carnitine and acylcarnitines, suggesting MCTs might not be metabolized independently of carnitine.11 Since carnitine deficiency can also impair ketogenesis, individuals consuming a ketogenic diet high in MCTs should be monitored for signs or symptoms suggestive of carnitine deficiency.

Davis et al have shown that very low calorie diets (between 420-600 kcal/day) can have a negative effect on both plasma and urinary carnitine levels. Although plasma shortchain acylcarnitine esters increased and free carnitine declined significantly, protein consumption appeared to exert a sparing effect on carnitine since individuals consuming a preponderance of calories as meat/fish/poultry maintained significantly higher levels of plasma total carnitine.12

Ascorbic acid is required for the biosynthesis of L-carnitine, so it is not surprising to find a deficiency of ascorbic acid will decrease endogenous biosynthesis of carnitine.13,14 Experimental evidence suggests some forms of vitamin B12 affect carnitine synthesis. In rats, administration of methylcobalamin, cyanocobalamin, and hydroxycobalamin have been shown to stimulate carnitine synthesis. This is probably due to the use of vitamin B12 in the re-methylation of homocysteine to methionine, since biochemically, SAM must donate methyl groups to complete the endogenous generation of carnitine from lysine.15 Although evidence is currently unavailable, it is possible deficiencies in other nutrients required for optimal levels of SAM, such as methionine, magnesium, folic acid, and betaine, might impair endogenous synthesis of L-carnitine.

Although the precise role of riboflavin (B2) in carnitine metabolism has not been elucidated, a case report suggests this vitamin might be an important component in optimizing carnitine levels in some individuals. In the report, Triggs et al describe a 29-year-old female with severe nausea and vomiting of pregnancy, migraines, psychiatric illness, non-epileptic seizures, and valproate-induced coma. Treatment with riboflavin normalized her plasma free carnitine level, and had a beneficial impact on her headaches and behavior.16

Since adequate dietary lysine is required as a substrate for carnitine synthesis, a deficiency of this amino acid or the other cofactors - iron, vitamin C, B6, niacin - might also compromise carnitine status.

Due to the choline-betaine pathway sharing an enzyme with the lysine to carnitine pathway, which was mentioned earlier,1,2 choline supplementation might decrease carnitine synthesis; therefore, it might be of greater benefit to supplement with betaine rather than its precursors, choline or phosphatidylcholine. In individuals consuming high amounts of choline, phosphatidylcholine, or lecithin (a rich source of phosphatidylcholine), additional supplementation of L-carnitine or an assessment of L-carnitine status might be warranted.

Drug Interactions

Anticonvulsant therapy, including phenobarbital, valproic acid, phenytoin, and carbamazepine, has a significant lowering effect on carnitine levels.17 Pivampicillin treatment is also known to negatively impact carnitine metabolism.18

L-carnitine should be used cautiously if at all with pentylenetetrazol, a respiratory stimulant drug, since evidence suggests the combination might enhance the side-effects of the drug.19

Evidence suggests L-carnitine might prevent the cardiac complications secondary to interleukin-2 immunotherapy in cancer patients.20 Experimental evidence also suggests L-carnitine might be able to prevent cardiac toxicity secondary to the administration of adriamycin.21 L-Carnitine, when used concurrently with zidovudine (AZT), appears to prevent the AZT-induced destruction of myotubules, preserve the structure and volume of mitochondria, and prevent the accumulation of lipids.22

Anorexia

In patients with anorexia nervosa, carnitine and adenosylcobalamin accelerated body weight gain and normalization of gastrointestinal function. Latent fatigue was reported to disappear and mental performance increase under this treatment regimen.23 Korkina et al reported the combined use of carnitine and adenosylcobalamin eliminated fluctuations in the work rate and improved the scope and productivity of intellectual work in patients with anorexia nervosa in the stage of cachexia, although latent fatigue in the population studied was not fully removed.24

Children with infantile anorexia also appear to respond well to a combination of carnitine and adenosylcobalamin. One group of children was given 2000 mcg adenosylcobalamin and 1000 mg carnitine, while the other group was given cyproheptadine, an anti-histamine used to stimulate appetite. Results of adenosylcobalamin and carnitine treatment were judged good by the authors, were comparable to the effects of the pharmaceutical agent, and were produced with no side-effects.25

Athletic Performance

Carnitine is promoted as a supplement needed to improve the body's ability to use stored fat as fuel. Supplementation purportedly enhances lipid oxidation, increases VO2 max, and decreases plasma lactate accumulation during exercise.

[...]

Siliprandi et al, in a small double-blind cross-over study of ten moderately-trained male subjects, gave either 2 grams of L-carnitine or placebo orally one hour prior to exercise. Supplementation with L-carnitine induced a significant post-exercise decrease of plasma lactate and pyruvate and a concurrent increase of acetylcarnitine.27 Vecchiet et al randomly gave 2 grams of L-carnitine or a placebo to subjects one hour before they began exercise. At the maximal exercise intensity, treatment with L-carnitine increased both maximal oxygen uptake and power output. The authors also reported, at similar, non-maximal, exercise intensities, participants receiving L-carnitine had reduced oxygen uptake, carbon dioxide production, pulmonary ventilation, and plasma lactate.28

While some of the results with L-carnitine supplementation have been promising, not all research is in agreement. Heinonen, in his review of carnitine supplementation and physical exercise, concluded that its impact on performance in athletes is equivocal: it does not enhance fatty acid oxidation, spare glycogen or postpone fatigue during exercise; it does not stimulate pyruvate dehydrogenase activity; and it does not reduce body fat or help with weight loss.29

[...]

Colambani et al investigated the effects of L-carnitine supplementation on metabolism and performance of endurance-trained athletes during and after a marathon run. In a doubleblind cross-over field study, seven male subjects received two grams of L-carnitine two hours before the start of a marathon run and again after 20 km of running. Although the administration of L-carnitine was associated with a significant increase in the plasma concentration of all analyzed carnitine fractions, significant changes in running time, plasma concentrations of carbohydrate metabolites (glucose, lactate, and pyruvate), as well as fat metabolites (free fatty acids, glycerol, and beta-hydroxybutyrate), hormones (insulin, glucagon, and cortisol), and enzyme activities (creatine kinase and lactate dehydrogenase) were not observed.33

[...]

Chronic Fatigue Syndrome and Mitochondrial Myopathy

Researchers investigating the oral administration of L-carnitine as a potential treatment for chronic fatigue syndrome observed clinical improvement in 12 of 18 patients. They also reported the trend for the greatest improvement occurred between weeks four and eight of treatment. One patient was unable to complete the trial due to the development of diarrhea.34

Campos et al found plasma carnitine "insufficiency," (defined as plasma esterified carnitine to free carnitine ratio above 0.25) in 21 of 48 (43.8%) patients with mitochondrial myopathy. They proceeded to treat the patients classified as "insufficient" with L-carnitine (50-200 mg/kg four times daily) and observed improvements in muscle weakness in 19 of 20 patients, failure to thrive in 4 of 8, encephalopathy in 1 of 9, and cardiomyopathy in 8 of 8 patients.35

[...]

Hypoglycemia

Since one of the manifestations of carnitine deficiency is hypoglycemia, it is not surprising that several investigators have reported a beneficial impact of L-carnitine administration on plasma glucose and insulin levels following intravenous infusion of glucose. Negro et al observed that the addition of both 2 g and 4 g of L-carnitine to 500 ml solutions of 5 percent and 10 percent glucose reduced the increase in plasma glucose levels.56 Grandi et al reported a similar improvement in glucose metabolism following the addition of 2 g of L-carnitine to a 5-percent glucose solution.57 Whether these observations would translate to a beneficial clinical effect in individuals with a tendency to reactive blood sugar is not currently known; however, due to the safety of L-carnitine and its tendency to improve fatigue (a common concomitant symptom of individuals with reactive blood sugar), a clinical trial with L-carnitine seems warranted.

Pregnancy and Pediatric Applications

Among the physiological changes characteristic of intrauterine development is an increase in body stores of carnitine, thought to occur due to the increased demand of the fetus on maternal supplies. Following delivery, interruption of the materno-fetal supply, along with the inability of the newborn to meet body requirements by endogenous synthesis, leaves the infant dependent upon exogenous intake. In circumstances of the absence of exogenous intake due to carnitine-free nutrition, tissue carnitine reserves decline in infants. Preterm infants are predictably in even greater jeopardy of having a relative carnitine deficiency.61 In contrast, a gradual increase of carnitine stores is a normal response of infants to breast feeding or the use of carnitine-containing formulas.62 Genger et al have reported an increased need for carnitine during pregnancy. In a small trial of women with diagnosed placental insufficiency, they observed a tendency toward beneficial outcomes following carnitine administration (1 g twice daily orally for one week followed by 1 g daily for the second week). In spite of the small numbers in this trial, the relative short duration of supplementation combined with the trend toward improved outcomes certainly merits further investigation of L-carnitine for this condition.63

Since physiologically, L-carnitine activates surfactant synthesis, it is not surprising that supplementation to women with imminent premature delivery provides a substantial benefit to the infant in the postnatal period. Results indicate a combination of L-carnitine (4 g/day for five days) and betamethasone given to women in the prenatal period can reduce both the incidence of respiratory distress syndrome and the mortality of premature newborns. In this trial, the incidence of respiratory distress syndrome of infants was approximately one-half (7.3% vs 14.5%) and the mortality rate was 1.8 percent compared with 7.3 percent in the group receiving the combined intervention as compared to betamethasone alone.64

In a case of three siblings presenting with apnea and periodic breathing, along with biochemical defects consistent with a non-specific abnormality of beta oxidation, one of the infants died of sudden infant death syndrome; however, the two surviving infants had a rapid resolution of both respiratory and metabolic abnormalities subsequent to treatment with Lcarnitine.65

Winter et al have suggested, based upon their clinical experience, that "secondary plasma carnitine deficiency is a common pediatric finding. The presence of failure to thrive, recurrent infections, hypotonia, encephalopathy, cardiomyopathy, or nonketotic hypoglycemia requires investigation of carnitine status."66 These authors reported normalization of cardiomyopathy in eight infants subsequent to the correction of a secondary L-carnitine deficiency. Kothari and Sharma have also reported a modest improvement in left ventricular function subsequent to administration of L-carnitine (50 mg/kg/day) in 13 children with idiopathic dilated cardiomyopathy.67

Progressive cardiomyopathy, with or without chronic muscle weakness, is the most common presentation (median age of onset, three years) in children with a defect in intracellular uptake of carnitine resulting in carnitine deficiency. Episodes of fasting hypoglycemia during the first two years of life are also a common presentation in affected infants. These children have low levels of plasma carnitine and a decreased rate of carnitine uptake. Typically, parents of affected children have intermediate values lying between those of normal control subjects and the affected children, suggestive of recessive inheritance. Stanley et al have suggested that early recognition of this disorder and the subsequent treatment with high doses of oral carnitine might be a lifesaving intervention for these children.68

Carnitine deficiency might be a complicating factor in cystic fibrosis. Wos et al reported five cases of infants with cystic fibrosis, impaired liver function, and neurological symptoms who, subsequent to a high carnitine diet and enteral administration, experienced a concomitant improvement in clinical condition with the progressive normalization of serum carnitine levels.69

Rett Syndrome

Two case reports in the medical literature indicate administration of L-carnitine might provide some benefits to individuals with Rett syndrome. Plioplys and Kasnicka treated a 17-year-old female with L-carnitine (50 mg/kg/day). Over the two-month course of treatment an improvement in alertness, eye contact, and interaction with her environment were observed. These improvements were all lost following discontinuation of L-carnitine, and were regained after L-carnitine was reintroduced.70

Researchers administered L-carnitine (beginning at 75 mg/kg/day and increasing to 150 mg/kg/day) to a 3 1/2-year-old girl diagnosed with Rett syndrome. They observed improvements in physical activity, muscle hypotonia, communication, and sleep time. Similar to the findings of Plioplys and Kasnicka, a wash-out period followed by reintroduction of L-carnitine supplementation confirmed the efficacy of this regime.71

Precautions

L-carnitine is listed as pregnancy category B, indicating animal studies have revealed no harm to the fetus, but that no adequate studies in pregnant women have been conducted. However, since L-carnitine has been given to pregnant women late in pregnancy with resulting positive outcomes and since L-carnitine is a normally occurring component of the diet, it is unlikely this supplement has any negative impact on pregnancy in normally supplemented amounts. In general, the recommendation for its use follows that of other nutritional substances which have not been overtly studied during human pregnancy; that being, use the supplement cautiously and only if clearly indicated by either laboratory or clinical status. The racemic mixture (D,L-carnitine) should be avoided. D-carnitine is not biologically active and might interfere with the proper utilization of the L isomer. In uremic patients, use of the racemic mixture has been correlated with myasthenia-like symptoms in some individuals.

Adverse Reactions

A variety of mild gastrointestinal symptoms have been reported, including transient nausea and vomiting, abdominal cramps, and diarrhea. A change in body odor has also been observed in a few individuals. Typically, reducing the dose will result in improvements in these adverse reactions.

No reports of L-carnitine toxicity from overdosage exist. In mice, the LD50 is 19.2 g/ kg. Studies indicate no mutagenicity; however, experiments to determine the long-term carcinogenicity have not been conducted.

Dosage

As a general guideline, the average therapeutic dose is 1000 mg given two to three times daily for a total of 2000-3000 mg. No advantage appears to exist in giving an oral dose greater than 2000 mg at one time, since absorption studies indicate saturation at this dose.

Conclusions

L-carnitine has been used as a nutritional supplement for more than two decades. Although it has a well-deserved reputation as a safe and effective addition to nutritional protocols for a range of clinical conditions, its therapeutic role in coronary disease is perhaps its primary claim to fame. Addition of L-carnitine to a protocol for angina and ischemia results in improved exercise tolerance, reduced frequency of angina episodes, and beneficial changes to the ECG. L-carnitine seems to predictably improve risk factor markers of coronary disease; however, the single most impressive aspect of L-carnitine supplementation in coronary conditions has been the consistent bottom-line impact in reducing the clinical end point of congestive heart failure mortality. With additional research now indicating a place for L-carnitine in assisting with clinically challenging conditions such as chronic fatigue syndrome, HIV, and hypoglycemia, and with the ever expanding role of L-carnitine in pediatric health, it appears the use of this dietary supplement will continue to expand.

References

1. Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr 1996;63:904-910.

2. Daily JW 3rd, Sachan DS. Choline supplementation alters carnitine homeostasis in humans and guinea pigs. J Nutr 1995;125:1938-1944.

3. Li B, Lloyd ML, Gudjonsson H, et al. The effect of enteral carnitine administration in humans. Am J Clin Nutr 1992;55:838-845.

4. Harper P, Elwin CE, Cederblad G. Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects. Eur J Clin Pharmacol 1988;35:555-562.

5. Bach AC, Schirardin H, Sihr MO, Storck D. Free and total carnitine in human serum after oral ingestion of L-carnitine. Diabete Metab 1983;9:121-124.

6. Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr 1991;121:539-546.

7. Sahajwalla CG, Helton ED, Purich ED, et al. Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers. J Pharm Sci 1995;84:627-633.

8. Baker H, Frank O, DeAngelis B, Baker ER. Absorption and excretion of L-carnitine during single or multiple dosings in humans. Int J Vitam Nutr Res 1993;63:22-26.

9. Etzioni A, Levy J, Nitzan M, et al. Systemic carnitine deficiency exacerbated by a strict vegetarian diet. Arch Dis Child 1984;59:177- 179.

10. Cederblad G. Effect of diet on plasma carnitine levels and urinary carnitine excretion in humans. Am J Clin Nutr 1987;45:725-729.

11. Rossle C, Carpentier YA, Richelle M, et al. Medium-chain triglycerides induce alterations in carnitine metabolism. Am J Physiol 1990;258:E944-E947.

12. Davis AT, Davis PG, Phinney SD. Plasma and urinary carnitine of obese subjects on verylow- calorie diets. J Am Coll Nutr 1990;9:261- 264.

13. Johnston CS, Solomon RE, Corte C. Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coll Nutr 1996;15:586-591.

14. Ha TY, Otsuka M, Arakawa N. The effect of graded doses of ascorbic acid on the tissue carnitine and plasma lipid concentrations. J Nutr Sci Vitaminol 1990;36:227-234.

15. Podlepa EM, Gessler NN, Bykhovskii VIa. The effect of methylation on the carnitine synthesis. Prikl Biokhim Mikrobiol 1990;26:179-183. [Article in Russian]

16. Triggs WJ, Roe CR, Rhead WJ, et al. Neuropsychiatric manifestations of defect in mitochondrial beta oxidation response to riboflavin. J Neurol Neurosurg Psychiatry 1992;55:209-211.

17. Hug G, McGraw CA, Bates SR, Landrigan EA. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802.

18. Melegh B, Pap M, Molnar D, et al. Carnitine administration ameliorates the changes in energy metabolism caused by short-term pivampicillin medication. Eur J Pediatr 1997;156:795-799.

19. Herink J. Enhancing effect of L-carnitine on some abnormal signs induced by pentylenetetrazol. Acta Medica 1996;39:63-66.

20. Lissoni P, Galli MA, Tancini G, Barni S. Prevention by L-carnitine of interleukin-2 related cardiac toxicity during cancer immunotherapy. Tumori 1993;79:202-204.

21. Kawasaki N, Lee JD, Shimizu H, Ueda T. Long-term L-carnitine treatment prolongs the survival in rats with adriamycin-induced heart failure. J Card Fail 1996;2:293-299.

22. Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102-112.

23. Korkina MB, Korchak GM, Medvedev DI. Clinico-experimental substantiation of the use of carnitine and cobalamin in the treatment of anorexia nervosa. Zh Nevropatol Psikhiatr 1989;89:82-87. [Article in Russian]

24. Korkina MV, Korchak GM, Kareva MA. Effects of carnitine and cobamamide on the dynamics of mental work capacity in patients with anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1992;92:99-102. [Article in Russian]

25. Giordano C, Perrotti G. Clinical studies of the effects of treatment with a combination of carnitine and cobamamide in infantile anorexia. Clin Ter 1979;88:51-60. [Article in Italian]

26. Swart I, Rossouw J, Loots JM, Kruger MC. The effect of L-carnitine supplementation on plasma carnitine levels and various performance parameters of male marathon athletes. Nutr Res 1997;17:405-414.

27. Siliprandi N, Di Lisa F, Pieralisi G, et al. Metabolic changes induced by maximal exercise in human subjects following Lcarnitine administration. Biochim Biophys Acta 1990;1034:17-21.

28. Vecchiet L, Di Lisa F, Pieralisi G, et al. Influence of L-carnitine administration on maximal physical exercise. Eur J Appl Physiol 1990;61:486-490.

29. Heinonen OJ. Carnitine and physical exercise. Sports Med 1996;22:109-132.

30. Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Med Sci Sports Exerc 1994;26:1122-1129.

31. Barnett C, Costill DL, Vukovich MD, et al. Effect of L-carnitine supplementation on muscle and blood carnitine content and lactate accumulation during high-intensity sprint cycling. Int J Sport Nutr 1994;4:280-288.

32. Cooper MB, Jones DA, Edwards RH, et al. The effect of marathon running on carnitine metabolism and on some aspects of muscle mitochondrial activities and antioxidant mechanisms. J Sports Sci 1986;4:79-87.

33. Colombani P, Wenk C, Kunz I, et al. Effects of L-carnitine supplementation on physical performance and energy metabolism of endurance-trained athletes: a double-blind crossover field study. Eur J Appl Physiol 1996;73:434-439.

34. Plioplys AV, Plioplys S. Amantadine and Lcarnitine treatment of chronic fatigue syndrome. Neuropsychobiology 1997;35:16-23.

35. Campos Y, Huertas R, Lorenzo G, et al. Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy. Muscle Nerve 1993;16:150-153.

36. Ramos AC, Barrucand L, Elias PR, et al. Carnitine supplementation in diphtheria. Indian Pediatr 1992;29:1501-1505.

37. Kamikawa T, Suzuki Y, Kobayashi A, et al. Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris. Jpn Heart J 1984;25:587-597.

38. Canale C, Terrachini V, Biagini A, et al. Bicycle ergometer and echocardiographic study in healthy subjects and patients with angina pectoris after administration of Lcarnitine: semiautomatic computerized analysis of M-mode tracing. Int J Clin Pharmacol Ther Toxicol 1988;26:221-224.

39. Cherchi A, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol 1985;23:569-572.

40. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res 1991;17:225-235.

41. Fernandez C, Proto C. L-carnitine in the treatment of chronic myocardial ischemia. An analysis of 3 multicenter studies and a bibliographic review. Clin Ter 1992;140:353-377. [Article in Italian]

42. Brevetti G, Chiariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with Lcarnitine: a double-blind, cross-over study. Circulation 1988;77:767-773.

43. Mondillo S, Faglia S, D’Aprile N, et al. Therapy of arrhythmia induced by myocardial ischemia. Association of L-carnitine, propafenone and mexiletine. Clin Ter 1995;146:769-774. [Article in Italian]

44. Corbucci GG, Lettieri B. Cardiogenic shock and L-carnitine: clinical data and therapeutic perspectives. Int J Clin Pharmacol Res 1991;11:283-293.

45. Corbucci GG, Loche F. L-carnitine in cardiogenic shock therapy: pharmacodynamic aspects and clinical data. Int J Clin Pharmacol Res 1993;13:87-91.

46. Ino T, Sherwood WG, Benson LN, et al. Cardiac manifestations in disorders of fat and carnitine metabolism in infancy. J Am Coll Cardiol 1988;11:1301-1308.

47. Ferro M, Crivello R, Gianotti A, Conti M. Treatment of hypertrophic cardiomyopathy with a combination of carnitine and beta blockaders. Review of the literature. Description of a clinical case and long-term follow up. Clin Ter 1993;143:109-113. [Article in Italian]

48. Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18:355-365. 49. De Pasquale B, Righetti G, Menotti A. Lcarnitine for the treatment of acute myocardial infarct. Cardiologia 1990;35:591-596. [Article in Italian]

50. Singh RB, Niaz MA, Agarwal P, et al. A randomised, double-blind, placebo-controlled trial of L-carnitine in suspected acute myocardial infarction. Postgrad Med J 1996;72:45-50.

51. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 1995;26:380-387.

52. Ghidini O, Azzurro M, Vita G, Sartori G. Evaluation of the therapeutic efficacy of Lcarnitine in congestive heart failure. Int J Clin Pharmacol Ther Toxicol 1988;26:217-220.

53. Moretti S, Alesse E, Di Marzio L, et al. Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood 1998;91:3817-3824.

54. Cifone MG, Alesse E, Di Marzio L, et al. Effect of L-carnitine treatment in vivo on apoptosis and ceramide generation in peripheral blood lymphocytes from AIDS patients. Proc Assoc Am Physicians 1997;109:146-153.

55. De Simone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12.

56. Negro P, Gossetti F, La Pinta M, et al. The effect of L-carnitine, administered through intravenous infusion of glucose, on both glucose and insulin levels in healthy subjects. Drugs Exp Clin Res 1994;20:257-262.

57. Grandi M, Pederzoli S, Sacchetti C. Effect of acute carnitine administration on glucose insulin metabolism in healthy subjects. Int J Clin Pharmacol Res 1997;17:143-147.

58. Lenzi A, Lombardo F, Gandini L, Dondero F. Metabolism and action of L-carnitine: its possible role in sperm tail function. Arch Ital Urol Nefrol Androl 1992;64:187-196. [Article in Italian]

59. Costa M, Canale D, Filicori M, et al. Lcarnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159.

60. Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159.

61. Melegh B. Carnitine supplementation in the premature. Biol Neonate 1990;58 Suppl 1:93-106. 61. Melegh B. Carnitine supplementation in the premature. Biol Neonate 1990;58 Suppl 1:93- 106.

62. Melegh B, Kerner J, Szucs L, Porpaczy Z. Feeding preterm infants with L-carnitine supplemented formula. Acta Paediatr Hung 1990;30:27-41.

63. Genger H, Enzelsberger H, Salzer H. Carnitine in therapy of placental insufficiency—initial experiences. Z Geburtshilfe Perinatol 1988;192:155-157. [Article in German]

64. Kurz C, Arbeiter K, Obermair A, et al. Lcarnitine- betamethasone combination therapy versus betamethasone therapy alone in prevention of respiratory distress syndrome. Z Geburtshilfe Perinatol 1993;197:215-219. [Article in German]

65. Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatr Pulmonol 1995;20:167-171.

66. Winter SC, Szabo-Aczel S, Curry CJ, et al. Plasma carnitine deficiency. Clinical observations in 51 pediatric patients. Am J Dis Child 1987;141:660-665.

67. Kothari SS, Sharma M. L-carnitine in children with idiopathic dilated cardiomyopathy. Indian Heart J 1998;50:59-61.

68. Stanley CA, DeLeeuw S, Coates PM, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991;30:709-716.

58. Lenzi A, Lombardo F, Gandini L, Dondero F. Metabolism and action of L-carnitine: its possible role in sperm tail function. Arch Ital Urol Nefrol Androl 1992;64:187-196. [Article in Italian]

59. Costa M, Canale D, Filicori M, et al. Lcarnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159.

60. Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159.

61. Melegh B. Carnitine supplementation in the premature. Biol Neonate 1990;58 Suppl 1:93-106.

62. Melegh B, Kerner J, Szucs L, Porpaczy Z. Feeding preterm infants with L-carnitine supplemented formula. Acta Paediatr Hung 1990;30:27-41.

63. Genger H, Enzelsberger H, Salzer H. Carnitine in therapy of placental insufficiency - initial experiences. Z Geburtshilfe Perinatol 1988;192:155-157. [Article in German]

64. Kurz C, Arbeiter K, Obermair A, et al. Lcarnitine-betamethasone combination therapy versus betamethasone therapy alone in prevention of respiratory distress syndrome. Z Geburtshilfe Perinatol 1993;197:215-219. [Article in German]

65. Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatr Pulmonol 1995;20:167-171.

66. Winter SC, Szabo-Aczel S, Curry CJ, et al. Plasma carnitine deficiency. Clinical observations in 51 pediatric patients. Am J Dis Child 1987;141:660-665.

67. Kothari SS, Sharma M. L-carnitine in children with idiopathic dilated cardiomyopathy. Indian Heart J 1998;50:59-61.

68. Stanley CA, DeLeeuw S, Coates PM, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991;30:709-716.

69. Wos H, Krauze M, Bujniewicz E, et al. Total carnitine level in infants with cystic fibrosis and deficit supplementation by means of pharmacologic preparations and diet. Introductory remarks. Pediatr Pol 1995;70:661-666. [Article in Polish]

70. Plioplys AV, Kasnicka I. L-carnitine as a treatment for Rett syndrome. South Med J 1993;86:1411-1412.

71. Plochl E, Sperl W, Wermuth B, Colombo JP. Carnitine deficiency and carnitine therapy in a patient with Rett syndrome. Klin Padiatr 1996;208:129-134. [Article in German]