INTRODUCTION

Carnitine is a chemical produced in the body, which is required for the passage of fatty acids across membranes of the mitochondria. There are two types - carnitine and acetyl-L-carnitine, the only difference between them is that acetyl-l-carnitine is absorbed more efficiently in the blood and is in overall more effective. It improves stress tolerance in damaged heart muscle in humans and it has anti-fatigue effects. Studies have shown that it has antioxidant properties also. The major sources of it are red meat and diary products.

Below you find a list of scientific abstracts on Carnitine from pubmed.

3-(2, 2, 2-trimethylhydrazinium) propionate (THP) inhibits gamma-butyrobetaine hydroxylase, which is accompanied by a drop in myocardial free carnitin content. In rabbits, 200 mg/kg THP, administered intraperitoneally for 10 days, decreases free carnitin and long-chain acylcarnitin by 59.8 and 59.2%, respectively. In a carnitin-depressing dose, THP helps to recover contractility of isolated atria after hypoxic exposure. THP prevents isoproterenol-induced accumulation of long-chain acylcarnitin and ATR fall in the rat myocardium. The protective effect of THP is realized in the presence of considerably reduced (by an average of 77.8%) myocardial free carnitin levels. Inhibition of carnitin-dependent fatty acids metabolism by reducing intracellular carnitin concentration is a pathogenetically justified method of myocardial protection against ischemic damage.

Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.

Careful review of all available clinical trials of L-carnitine leads to the conclusion that there is insufficient evidence to support the routine use of L-carnitine for any indication in dialysis patients. The literature suffers from a lack of adequately designed studies, and many of the studies which supposedly justify payment for L-carnitine supplementation are more than 10 years old. While some studies support a subjective improvement in symptoms after a few months of L-carnitine treatment, there is little confirming objective data. Biochemical parameters show minimal, if any, improvements. A major criticism is that many of the reported symptoms could be attributable to anemia, which at the time the L-carnitine studies were taking place, was generally being corrected with EPO. On the other hand, there is little data to support the hypothesis that L-carnitine enhances the response to EPO or overcomes EPO resistance. The decrease in the use of L-carnitine in the past several years may be related in part to difficulty with reimbursement. The decrease also suggests that practitioners have abandoned the hypothesis that L-carnitine supplementation provides substantial clinical benefits, and therefore no longer prescribe it for dialysis patients. For those physicians who plan to prescribe L-carnitine based on the recent CMS reimbursement decision, it must be remembered that the laboratory measurement of free carnitine may be difficult and inaccurate. For those patients with private insurance, payment for the lab test is out of pocket. If the free carnitine level is measured once dialysis starts, a value in the CMS "deficient" range can occur since carnitine drops early in the dialysis procedure and slowly rebounds after the treatment. Therefore, it is critical that the measurement be done pre-dialysis after a three-day interdialytic interval to obtain the most accurate value. If strict guidelines for use of L-carnitine are adhered to (i.e., the patient has true EPO-resistant anemia unexplained by any identifiable factor and true unexplained hypotension), then the use of L-carnitine in ESRD patients should be very uncommon. In conclusion, the clinical value of L-carnitine supplementation in hemodialysis patients remains to be documented by credible evidence from rigorous scientific studies. While "proof beyond a reasonable doubt" need not always be the requirement for reimbursement from payers, at a minimum "a preponderance of the evidence" should be documented in the literature. L-carnitine may prove to be a beneficial supplement. However, before justifying a national coverage policy, a new randomized, prospective controlled trial should be conducted to determine the utility of i.v. L-carnitine supplementation for anemia management and refractory dialysis-associated hypotension. Cost-benefit analysis is a critical aspect of such a study because it is important to determine the total cost (no matter who pays) of L-carnitine supplementation as compared to money saved by a reduction in EPO and iron administration. When reimbursement policies are developed, they need to be rational and based on the best evidence that is available. An NKF Carnitine Consensus Conference concluded that current literature and clinical experience leave unanswered questions regarding the use of L-carnitine in dialysis patients. Until there is scientific evidence to support use of L-carnitine supplementation, and it proves to be cost-effective, reimbursement is not justified. Therefore, the current CMS reimbursement decision for L-carnitine appears to be flawed.

Carnitine and hemodialysis.
Bellinghieri G, Santoro D, Calvani M, Mallamace A, Savica V.
Division of Nephrology, University of Messina, Italy.
Am J Kidney Dis. 2003 Mar;41(3 Suppl 2):S116-22

Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic. It is an important element in the beta-oxidation of fatty acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic membranes, leading in some patients to carnitine depletion with a relative increase of esterified forms. The authors found a decrease in plasma-triglyceride and increase of high-density lipoprotein cholesterol (HDL-Chol) in dialysis patients during carnitine treatment. Many studies have shown that L-carnitine supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells. In addition, carnitine supplementation may improve protein metabolism and insulin resistance. Recently, carnitine supplementation has been approved by the US Food and Drug Administration not only for the treatment, but also for the prevention of carnitine depletion in dialysis patients. Regular carnitine supplementation in hemodialysis patients can improve their lipid metabolism, protein nutrition, antioxidant status, and anemia requiring large doses of erythropoietin, It also may reduce the incidence of intradialytic muscle cramps, hypotension, asthenia, muscle weakness, and cardiomyopathy.

OBJECTIVE: Systemic carnitine deficiency may present with apnea, hypotonia, and poor growth. Premature infants often manifest these symptoms and are at risk of developing carnitine deficiency because of immaturity of the biosynthetic pathway, lack of sufficient predelivery transplacental transport, and lack of sufficient exogenous supplementation. This study was undertaken to examine the effect of carnitine supplementation in premature infants. METHODS: Eighty preterm infants <1500 g were enrolled in a prospective, double-blind, placebo-controlled study of carnitine supplementation within 96 hours of delivery. Growth, length of hospital stay, and frequency and severity of apnea were the primary outcome measures. RESULTS: Weight gain and change in length, fronto-occipital head circumference, mid arm circumference, and triceps skinfold thickness were similar between the carnitine-supplemented and placebo groups. The amount and severity of apnea and the overall length of hospitalization were also similar between the 2 groups. The carnitine levels in the supplemented group were significantly higher than in the placebo group at 4 and 8 weeks after study entry. CONCLUSION: Although preterm infants <1500 g have low carnitine levels, routine supplementation with carnitine has no demonstrable effect on growth, apnea, or length of hospitalization and thus seems to be unnecessary.

OBJECTIVE: To determine the efficacy of L-carnitine therapy in selected cases of male factor infertility. DESIGN: Placebo-controlled, double-blind, crossover trial. SETTING: University tertiary referral center. PATIENT(S): One hundred infertile patients (ages 20-40 years) with the following baseline sperm selection criteria: concentration, 10-20 x 10(6)/mL; total motility, 10%-30%; forward motility, <15%; atypical forms, <70%; velocity, 10-30 micro/s; linearity, <4. Eighty-six patients completed the study. INTERVENTION(S): Patients underwent L-carnitine therapy 2 g/day or placebo; the study design was 2 months of washout, 2 months of therapy/placebo, 2 months of washout, and 2 months placebo/therapy. MAIN OUTCOME MEASURE(S): Variation in sperm parameters used in the patients selection criteria, in particular, sperm motility.Excluding outliers, a statistically significant improvement in semen quality, greater than after the placebo cycle, was seen after the L-carnitine therapy for sperm concentration and total and forward sperm motility. The increase in forward sperm motility was more significant in those patients with lower initial values, i.e., <5 x 10(6) or <2 x 10(6) of forward motile sperm/ejaculate or sperm/mL. CONCLUSION(S): Based on a controlled study of efficacy, L-carnitine therapy was effective in increasing semen quality, especially in groups with lower baseline levels. However, these results need to be confirmed by larger clinical trials and in vitro studies.

L-carnitine (LC) plays an essential metabolic role that consists in transferring the long chain fatty acids (LCFAs) through the mitochondrial barrier, thus allowing their energy-yielding oxidation. Other functions of LC are protection of membrane structures, stabilizing a physiologic coenzyme-A (CoA)-sulfate hydrate/acetyl-CoA ratio, and reduction of lactate production. On the other hand, numerous observations have stressed the carnitine ability of influencing, in several ways, the control mechanisms of the vital cell cycle. Much evidence suggests that apoptosis activated by palmitate or stearate addition to cultured cells is correlated with de novo ceramide synthesis. Investigations in vitro strongly support that LC is able to inhibit the death planned, most likely by preventing sphingomyelin breakdown and consequent ceramide synthesis; this effect seems to be specific for acidic sphingomyelinase. The reduction of ceramide generation and the increase in the serum levels of insulin-like growth factor (IGF)-1, could represent 2 important mechanisms underlying the observed antiapoptotic effects of acetyl-LC. Primary carnitine deficiency is an uncommon inherited disorder, related to functional anomalies in a specific organic cation/carnitine transporter (hOCTN2). These conditions have been classified as either systemic or myopathic. Secondary forms also are recognized. These are present in patients with renal tubular disorders, in which excretion of carnitine may be excessive, and in patients on hemodialysis. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic membranes, leading, in some patients, to carnitine depletion with a relative increase in esterified forms. Many studies have shown that LC supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells.

We sought to determine the effects of supplementary choline, carnitine and a combination of the two with or without exercise on serum and urinary carnitine and biochemical markers of fatty acid oxidation in healthy humans. Nineteen women were placed in three groups: 1) placebo, choline or carnitine preloading period of 1 wk followed by 2) supplementation with choline plus carnitine during wk 2-wk 3 and 3) all groups exercised in wk 3. Although there were no changes in the placebo group, serum and urinary carnitine decreased in the choline-supplemented group during wk 1. Introduction of carnitine to the choline group restored serum and urinary carnitine. Serum and urinary carnitine increased during wk 1 in the carnitine-supplemented group and, although the introduction of choline to this group depressed serum and urinary carnitine, they remained significantly greater than control. Serum beta-hydroxybutyrate and serum as well as urinary acetylcarnitine were elevated by the supplements. A mild exercise regimen increased the concentration of serum beta-hydroxybutyrate, and serum and urinary acylcarnitines; it also decreased serum leptin concentrations in all groups. The effects of supplements were sustained until wk 2 after cessation of choline plus carnitine supplementation and exercise. We conclude that the choline-induced decrease in serum and urinary carnitine is buffered by carnitine preloading, and these supplements shift tissue partitioning of carnitine that favors fat mobilization, incomplete oxidation of fatty acids and disposal of their carbons in urine as acylcarnitines in humans.

Despite an abundance of literature describing the basic mechanisms of action of L-carnitine metabolism, there remains some uncertainty regarding the effects of oral L-carnitine supplementation on in vivo fatty acid oxidation in normal subjects under normal conditions. It is well known that L-carnitine normalizes the metabolism of long-chain fatty acids in cases of carnitine deficiency. However, it has not yet been shown that L-carnitine influences the metabolism of long-chain fatty acids in subjects without disturbances in fatty acid metabolism. Therefore, we investigated the effects of oral L-carnitine supplementation on in vivo long-chain fatty acid oxidation by measuring 1-[(13)C] palmitic acid oxidation in healthy subjects before and after L-carnitine supplementation (3 x 1 g/d for 10 days). We observed a significant increase in (13)CO(2) exhalation. This is the first investigation to conclusively demonstrate that oral L-carnitine supplementation results in an increase in long-chain fatty acid oxidation in vivo in subjects without L-carnitine deficiency or without prolonged fatty acid metabolism.

OBJECTIVE: To review the pathophysiology and significance of valproic acid-induced carnitine deficiency; to present and evaluate the literature pertaining to carnitine supplementation in pediatric patients receiving valproic acid; and to present the consensus guidelines for carnitine supplementation during valproic acid therapy. DATA SOURCES: A MEDLINE search (1966-December 1998) restricted to English-language literature, using MeSH headings of carnitine and valproic acid, was conducted to identify clinically relevant articles. Selected articles and references focusing on the pediatric population were included for review. DATA EXTRACTION: Study design, patient population, methods, and clinical outcomes were evaluated. DATA SYNTHESIS: Valproic acid, a widely used antiepileptic agent in the pediatric population, is limited by a 1/800 incidence of fatal hepatotoxicity in children under the age of two years. Carnitine is an essential amino acid necessary in beta-oxidation of fatty acids and energy production in cellular mitochondria. It has been hypothesized that valproic acid may induce a carnitine deficiency in children and cause nonspecific symptoms of deficiency, hepatotoxicity, and hyperammonemia. Relevant published case reports and trials studying this relationship are evaluated, and a consensus statement by the Pediatric Neurology Advisory Committee is reviewed. CONCLUSIONS: Despite the lack of prospective, randomized clinical trials documenting efficacy of carnitine supplementation in preventing valproic acid-induced hepatotoxicity, the few limited studies available have shown carnitine supplementation to result in subjective and objective improvements along with increases in carnitine serum concentrations in patients receiving valproic acid. The Pediatric Neurology Advisory Committee in 1996 provided more concrete indications on the role of carnitine in valproic acid therapy, such as valproic acid overdose and valproic acid-induced hepatotoxicity. Carnitine was strongly recommended for children at risk of developing a carnitine deficiency. Although carnitine has been well tolerated, future studies are needed to evaluate the efficacy of prophylactic carnitine supplementation for the prevention of hepatotoxicity.

Carnitine is critical for normal skeletal muscle bioenergetics. Carnitine has a dual role as it is required for long-chain fatty acid oxidation, and also shuttles accumulated acyl groups out of the mitochondria. Muscle requires optimization of both of these metabolic processes during peak exercise performance. Theoretically, carnitine availability may become limiting for either fatty acid oxidation or the removal of acyl-CoAs during exercise. Despite the theoretical basis for carnitine supplementation in otherwise healthy persons to improve exercise performance, clinical data have not demonstrated consistent benefits of carnitine administration. Additionally, most of the anticipated metabolic effects of carnitine supplementation have not been observed in healthy persons. The failure to demonstrate clinical efficacy of carnitine may reflect the complex pharmacokinetics and pharmacodynamics of carnitine supplementation, the challenges of clinical trial design for performance endpoints, or the adequacy of endogenous carnitine content to meet even extreme metabolic demands in the healthy state. In patients with end stage renal disease there is evidence of impaired cellular metabolism, the accumulation of metabolic intermediates and increased carnitine demands to support acylcarnitine production. Years of nutritional changes and dialysis therapy may also lower skeletal muscle carnitine content in these patients. Preliminary data have demonstrated beneficial effects of carnitine supplementation to improve muscle function and exercise capacity in these patients. Peripheral arterial disease (PAD) is also associated with altered muscle metabolic function and endogenous acylcarnitine accumulation. Therapy with either carnitine or propionylcarnitine has been shown to increase claudication-limited exercise capacity in patients with PAD. Further clinical research is needed to define the optimal use of carnitine and acylcarnitines as therapeutic modalities to improve exercise performance in disease states, and any potential benefit in healthy individuals.

We studied the effect of carnitine supplementation in patients with diphtheria. Six hundred and twenty five children of diphtheria received either DL-carnitine (100 mg/kg/day in two divided doses orally for four days), or no carnitine, in addition to the routine treatment for diphtheria. The patients receiving carnitine (n = 327) and controls (n = 298) were matched for age, sex, duration of symptoms, grade of toxemia and immunization status. Patients receiving carnitine showed a significant reduction in incidence of myocarditis as compared to controls (p = 0.001). Cases with myocarditis receiving carnitine therapy showed a significant reduction in mortality as compared to controls (p < 0.001). In view of a significant decline in incidence and mortality of myocarditis in cases of diphtheria, we recommended that all cases with diphtheria should receive carnitine supplementation.

The use of supplementary L-carnitine by athletes has become rather widespread over the recent years even in the absence of unequivocal results from human experimental studies that might support this practice. To justify the above procedure, the most commonly purported reasons are that L-carnitine administration could hypothetically: 1. increase lipid turnover in working muscles leading to glycogen saving and, as a consequence, allow longer performances for given heavy work loads; 2. contribute to the homeostasis of free and esterified L-carnitine in plasma and muscle, the allegation being that the levels of one or more of these compounds may decrease in the course of heavy repetitive exercise. A critical survey of the literature on carnitine metabolism in healthy humans at exercise does not appear to be available. The authors are of the opinion that this paper, besides shedding light into some relevant aspects of energy turnover in muscle, could also be of practical use not only for the physiologists but particularly for the Sport Medicine practitioners.

BACKGROUND: Long-term administration of high oral doses of L-carnitine on the skeletal muscle composition and the physical performance has not been studied in humans. METHODS: Eight healthy male adults were treated with 2 x 2 g of L-carnitine per day for 3 months. Muscle biopsies and exercise tests were performed before, immediately after, and 2 months after the treatment. Exercise tests were performed using a bicycle ergometer for 10 min at 20%, 40%, and 60% of the individual maximal workload (P(max)), respectively, until exhaustion. RESULTS: There were no significant differences between V(O(2)max), RER(max), and P(max) between the three time points investigated. At submaximal intensities, the only difference to the pretreatment values was a 5% increase in V(O(2)) at 20% and 40% of P(max) 2 months after the cessation of the treatment. The total carnitine content in the skeletal muscle was 4.10 +/- 0.82 micromol/g before, 4.79 +/- 1.19 micromol/g immediately after, and 4.19 +/- 0.61 micromol/g wet weight 2 months after the treatment (no significant difference). Activities of the two mitochondrial enzymes citrate synthase and cytochrome oxidase, as well as the skeletal muscle fiber composition also remained unaffected by the administration of L-carnitine. CONCLUSIONS: Long-term oral treatment of healthy adults with L-carnitine is not associated with a significant increase in the muscle carnitine content, mitochondrial proliferation, or physical performance. Beneficial effects of the long-term treatment with L-carnitine on the physical performance of healthy adults cannot be explained by an increase in the carnitine muscle stores.

BACKGROUND: Recent studies have shown that L-carnitine may improve clinical status and reduce the need for erythropoietin in dialysis patients with cardiovascular diseases. In this observational study, we investigated whether the addition of L-carnitine to conventional therapy might improve cardiac function (as assessed by M-mode and two-dimensional echocardiography) and clinical status in dialysis patients with left ventricular dysfunction. METHODS: Eleven dialysis patients with reduced left ventricular function (EF < 45%) were treated with L-carnitine for 8 months. Two-dimensional (2-D) echocardiography was performed at baseline and every 2 months up to the end of the treatment period. The dosage of erythropoietin was also monitored during the study and the patients' clinical status was assessed by a questionnaire. RESULTS: Carnitine increased mean LV ejection fraction from 32.0% to 41.8% (p < 0.05 vs baseline). There was also a slight reduction of erythropoietin dosage and an improvement of clinical status. CONCLUSIONS: Eight months' therapy with carnitine appears to improve LV function and clinical status in dialysis patients with impaired LVF.

BACKGROUND: Hepatitis C virus (HCV) is one of the major agents of chronic hepatitis and liver disease worldwide. Infection with HCV leads to chronic hepatitis in about 80% of the cases. The most used treatment is based on interferon (IFN)-alpha, which is effective in less than 50% of patients; however, a high proportion of responders may relapse after interferon withdrawal. Fatigue is a common complaint in patients with liver disease. The aim of our study was to evaluate the efficacy of carnitine on IFN-induced fatigue in subjects with chronic hepatitis C. PATIENTS AND METHODS: We studied 50 patients (30 males and 20 females) with chronic hepatitis C. Chronic hepatitis was diagnosed by determination of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (at least 2-fold upper normal values for 1 year). Our study series was divided into two groups and matched as to number, age, sex, as well as grade and duration of disease. Group 1, composed of 25 patients, was treated with leucocytic IFN-alpha at a dosage of 3 million IU thrice a week; group 2 (25 patients) was treated with the same protocol as group 1, but was also administered carnitine 2 g per os daily. Patients' response was evaluated on the basis of serum levels of AST and ALT as well as liver functions; fatigue was evaluated by Wessely and Powell scores. All patients studied were tested before treatment and then 1, 3 and 6 months after the beginning of IFN administration. RESULTS: The difference of physical fatigue between the two groups after 1 month of therapy was significant (p < 0.01) for patients treated with carnitine. This significance continued at the end of month 3 (p < 0.01). With reference to mental fatigue, the comparison between the two groups showed a significant difference for group 2 after 1 month (p < 0.01). Finally, with respect to the fatigue severity, the comparison between the two groups showed that after 1 and 3 months of therapy, fatigue was significantly less severe in group 2 than group 1 (p < 0.0005). CONCLUSIONS: If we take into account baseline values of mental and physical fatigue as well as the severity of this symptom in our study series, one observes that therapy with IFN alone induces fatigue in the majority of cases after 1 and 3 months, while at month 6, the values decrease. In contrast, patients treated with IFN + carnitine show a marked and early significant reduction of fatigue levels. These data suggest that the greater energetic substrate utilised by group 2 patients may in some way provide a better response of the patients to this side-effect. Abnormalities of neurotransmission concerning serotonine seem involved in the genesis of depression and fatigue. In addition, depression and fatigue commonly occur together, and the former is the most commonly observed symptom in patients with chronic fatigue syndrome.