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Carnitine

Nutrient Name: Carnitine.
Synonyms:L-Carnitine, levocarnitine; vitamin BT.
Forms: Acetyl-L-carnitine (ALC),L-acetylcarnatine (LAC); propionyl-L-caritine (PLC),L-propionylcarnitine (LPC).
Related Substance:D-Carnitine (synthetic isomer).

Summary Table
nutrient description

Chemistry and Forms

Carnitine (3-hydroxy-4N-trimethylammoniumbutanoate) is a naturally occurring quaternary amine. Forms include acetyl-L-carnitine (ALC;L-acetylcarnitine, LAC) and propionyl-L-carnitine (PLC;L-propionylcarnitine, LPC).

Physiology and Function

Carnitine (levocarnitine,L-carnitine) is considered to be a nonessential amino acid, although in certain situations it is considered conditionally essential (e.g., dialysis patients, premature and very-low-birth-weight infants, coronary artery disease). The highest concentrations of carnitine are found in the heart, muscles, liver, and kidney. The major biochemical function of carnitine is to act as a transmembrane carrier of long-chain fatty acids to the interior of mitochondria. It plays a major role in the utilization of fats in energy production at the mitochondrial level through the beta-oxidation of branched-chain amino acids and ketoacids. Carnitine also participates in transportation of acyl-coenzyme A (CoA) compounds. The activated long-chain fatty acyl-CoA esters in the cytosol are able to be transported to the mitochondrial matrix only by combining with carnitine. Beta-oxidation, the primary metabolic process by which fatty acids, branched-chain amino acids, and ketoacids (as acyl-coA esters) are used as fuel for cellular energy, occurs in the mitochondria. Thus, carnitine functions as an important physiological mediator of fatty acid and protein metabolism. Carnitine also enables hepatic detoxification and excretion of chemicals, including drugs, and improves glucose disposal and may reduce insulin resistance. Carnitine is instrumental in the production and release of acetylcholine.

Carnitine from dietary sources is rapidly absorbed from the intestinal tract by both passive and active transport. Although it exhibits vitamin-like properties, carnitine is a small amino acid derivative that can be synthesized de novo in the liver, brain, and kidneys using lysine and methionine in a process requiring vitamins C, B6, and niacin. Exogenous intake may be necessary during periods of increased demand or increased loss. Acetyl-L-carnitine (ALC), the acetylated derivative ofL-carnitine, is particularly localized in muscles, brain, and testicles.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Carnitine's central role in muscle function and fat metabolism has drawn the attention of clinicians and researchers to clinical applications related to these roles. Carnitine is proposed for increasing endurance and improving cardiac performance based on its known action of enhancing the efficiency of energy production in muscle tissue in general and the myocardium in particular. Human research has focused on therapeutic application of carnitine, especially as propionyl-L-carnitine (PLC), in the treatment of angina, myocardial insufficiency, peripheral claudication, and other conditions related to arterial insufficiency. CardiacL-carnitine content, essential for mitochondrial fatty acid transport and adenosine triphosphate (ATP)–diphosphate (ADP) exchange, decreases during ischemia. Furthermore, acetyl-L-carnitine (ALC) has been administered for slowing, and even partially reversing, nerve and brain deterioration associated with the aging process. Thus, the primary potential clinical uses for carnitine include claudication, Alzheimer's disease, myocardial insufficiency, and renal dialysis. Hyperlipidemia, male infertility, athletic performance, and weight loss have also been the subjects of therapeutic claims and evolving investigations, although results have been more mixed.

During pregnancy, infancy, and breastfeeding (i.e., situations of high energy demands), the physiological need forL-carnitine can exceed the capacity for endogenous synthesis. Consequently,L-carnitine is often used as a supplement with breast milk or infant formula for low-birth-weight (LBW) infants (either preterm or full term).

Possible Uses

Attention deficit–hyperactivity disorder (ADHD), alcohol dependence, Alzheimer's disease, angina pectoris, anorexia nervosa, arrhythmias, atherosclerosis, athletic performance (enhancement), cardiac ischemia, cardiac surgery (recovery), cataracts, chronic fatigue syndrome, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF; propionyl-L-carnitine), dementia, depression in elderly (acetyl-L-carnitine), diabetes mellitus, diabetic cardiac autonomic neuropathy, erectile dysfunction, human immunodeficiency virus (HIV) infection, hyperactivity in fragile X syndrome, hypercholesterolemia, hyperthyroidism, hypertriglyceridemia, infertility (male), intermittent claudication, myocardial infarction, myocardial insufficiency (e.g., CHF or cardiomyopathy), Peyronie's disease, Raynaud's disease, renal dialysis, seizure disorders, weight loss.

Deficiency Symptoms

Carnitine deficiency is characterized by inadequate tissue levels, resulting in impaired tissue fatty acid oxidation. Other symptoms of a relative deficiency may include elevated blood lipids, abnormal liver function, chronic muscle weakness, reduced energy, impaired glucose control, cardiomyopathy, encephalopathy, and recurrent episodes of coma. 1

Absolute carnitine deficiency is unlikely because of endogenous synthesis. Primary systemic carnitine deficiency is caused by a defect in the specific high-affinity carnitine transporter, which is expressed in most tissues and is responsible for bringing carnitine into the cytosol. This carnitine uptake defect is rare and is characterized by progressive infantile-onset carnitine-responsive cardiomyopathy, weakness, recurrent hypoglycemic hypoketotic encephalopathy, and failure to thrive. 2 Several inherited metabolic disorders, especially organic acidurias and disorders of beta-oxidation, can cause secondary carnitine deficiency. 3,4

Carnitine deficiency can result from numerous factors, independently or in combination, and will contribute to further sequelae and increased risk factors. Deficiency can result from high fat diets and insufficient supply of precursors for synthesis (methionine, lysine, niacin, vitamins C and B6). Individuals who have a limited intake of meat and dairy products tend to have lowerL-carnitine intakes. However, even long-term vegans usually do not display signs of carnitine deficiency. Seizure disorders, diabetes mellitus, cirrhosis, illness, and infection (e.g., HIV), strenuous exercise, trauma, pregnancy and lactation, and other conditions characterized by increased physiological stress are associated with decreased carnitine levels. A carnitine deficiency can also result from oxygen deprivation, which can occur in some cardiac conditions. 5 Carnitine deficiency may play a role in the development of retinopathy, hyperlipidemia, neuropathy, or complications of diabetes. 6 Many prescription medications may also have an adverse effect on carnitine levels and functions.

Dietary Sources

As implied by its name, carnitine is primarily found in foods of animal origin, and to a lesser extent, in foods of plant origin. Meat, milk, eggs, and dairy products are the richest sources of dietary carnitine intake, with beef being the most abundant. Generally, the redder the meat, the higher is the carnitine content. Cereals, fruit, and vegetables are relatively poor dietary sources.

Nutrient Preparations Available

Carnitine is administered as one of three salts ofL-carnitine:L-carnitine (for heart and other conditions), propionyl-L-carnitine (for heart conditions), and acetyl-L-carnitine (for Alzheimer's disease). The dosage is the same for all three forms, typically 500 mg to 1 g three times daily.

  • Note:   Only pureL-carnitine should be used as a supplement or therapeutic agent.

Dextrocarnitine (D-carnitine), or theDL-mixture, may interfere with the normal function of the levo (L-) isomer and produce signs of deficiency.

Dosage Forms Available

Capsule, powder, tablet.

Source Materials for Nutrient Preparations

Synthesized.

Dosage Range

Adult

  • Dietary:   No dietary reference intake (DRI) or recommended dietary allowance (RDA) has been established for carnitine. The average omnivorous diet provides approximately 100 to 300 mg of carnitine per day.
  • Supplemental/Maintenance:   1500 to 4000 mg per day in divided doses, when supplementation is indicated. Optimal levels of intake have not been established.
  • Pharmacological/Therapeutic:   150 mg to 1 g three times daily.
  • Toxic:   No toxicities have been reported or suspected as being associated with carnitine.

Pediatric (<18 Years)

  • Dietary:   No DRI or RDA has been established for carnitine.
  • Supplemental/Maintenance:   Usually not necessary, although often administered to LBW infants (preterm or full term) with breast milk or infant formula and in children receiving long-term total parenteral nutrition (TPN). Optimal levels of intake have not been established.
  • Pharmacological/Therapeutic:   50 mg to 1 g three times daily. One clinical trial involving children diagnosed with ADHD used 50 mg/kg twice daily, up to a maximum of 4 g daily. 7
  • Toxic:   No reported adverse effects have been specifically related to children.

safety profile

Overview

L-Carnitine is quite safe, with no significant adverse effects reported, even at high doses.

Nutrient Adverse Effects

General Adverse Effects

Rarely, gastrointestinal (GI) complaints such as nausea and vomiting have been reported with the use ofL-carnitine. 8 Sleeplessness may occur if taken before bed.

Pregnancy and Nursing

Adverse effects are not predicted, and reports are lacking. However, the lack of controlled studies involving pregnant or lactating women prevents any claims of safety and suggests that supplementation should be avoided during such life stages.

Infants and Children

Adverse effects are not predicted, and reports are lacking. Supplementation is not recommended unless otherwise indicated as essential.

Contraindications

Individuals with low or borderline-low thyroid levels should avoid carnitine supplementation because it may impair the action of thyroid hormone. 9,10This proposed effect is primarily extrapolated from research involving patients being treated for goiter with exogenous hormone.

Precautions and Warnings

DL-Carnitine may produce muscle weakness; theDisomer should be avoided because it may interfere with the activity ofL-carnitine and thus is potentially toxic.

interactions review

Strategic Considerations

The activity of carnitine suggests significant potential in preventing and treating many conditions, particularly in supporting healthy cardiovascular function. Combination therapy with a statin drug can be particularly effective in reducing lipoprotein(a) levels, especially in patients with type 2 diabetes. However, several common medications and drug classes can increase carnitine excretion or interfere with its activity. Continued development of carnitine therapy in treatment of ischemic disease is probable given its potential to limit anoxic damage while simultaneously reducing peripheral arterial resistance. 11 Furthermore, it may inhibit platelet-activating factor (PAF), thus potentially contributing an antithrombotic effect. Arterial insufficiency can decrease carnitine content of heart muscle cells. Carnitine is used conventionally in critical care and cancer surgery and has been found to benefit elderly and other high-risk patients undergoing elective cardiac surgery. 12

In regard to neurological conditions and carnitine, emerging evidence supports further research into its value in treating individuals with Alzheimer's disease. 13 Anticonvulsant medications tend to increase carnitine excretion, thus suggesting a potential role for coadministration in seizure disorders. Its immune-enhancing activity and potential efficacy during infections is countered by the adverse effects exerted on it by some chemotherapeutic agents and antiviral drugs, especially antiretroviral nucleoside analogs. Carnitine inhibits entry of thyroid hormone into certain cells and can be used to prevent adverse effects of thyroid therapy for goiter. 9,10

nutrient-drug interactions
Allopurinol
Doxorubicin and Related Anthracycline Chemotherapy
Isotretinoin and Related Retinoids
Levothyroxine and Related Thyroid Hormones
Nitroglycerin and Related Nitrates
Pivalate Prodrugs
Simvastatin and Related HMG-COA Reductase Inhibitors (Statins)
Valproic Acid and Related Anticonvulsant Medications
  • Evidence: Divalproex semisodium, divalproex sodium (Depakote), sodium valproate (Depacon), valproate semisodium, valproic acid (Depakene, Depakene Syrup).
  • Extrapolated, based on similar properties: Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), diazepam (Valium), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), gabapentin (Neurontin), levetiracetam (Keppra), mephenytoin, mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), phenobarbital (phenobarbitone; Luminal, Solfoton), phensuximide (Milontin), phenytoin (diphenylhydantoin; Dilantin, Phenytek), piracetam (Nootropyl), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), trimethadione (Tridione), vigabatrin (Sabril), zonisamide (Zonegran).
Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
Prevention or Reduction of Drug Adverse Effect
Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable to 1. Certain
Evidence Base: Mixed to Consensus

Effect and Mechanism of Action

Significant but incomplete evidence indicates that valproic acid (VPA) depresses renal absorption of both free carnitine and acylcarnitine. Other anticonvulsants appear to depress renal absorption of acylcarnitine only. Carnitine depletion may play a central role in the hepatotoxicity of VPA as well as the interference with fatty acid oxidation widely recognized as an adverse effect of VPA. Antiepileptic drugs (AEDs) may also affect carnitine and its functions by other mechanisms.

Research into the pharmacokinetics of VPA's adverse impact on free-carnitine levels suggest accelerated hepatic degradation of VPA as a result of enzyme induction with VPA metabolism. 59 VPA is extensively metabolized by the liver through glucuronic conjugation and oxidative pathways (P450) to produce biologically active metabolites. Half-life can range from 5 to 24 hours because of first-order kinetics. The three major metabolites of VPA are 2-EN-VPA, 4-EN-VPA, and propionic acid derivatives. The 4-EN-VPA may mediate reversible hepatotoxicity, which causes elevation of aminotransferases. Propionic acid derivatives may precipitate hyperammonemia by three different mechanisms, one of which is by interacting with carnitine, acting as a mitochondrial cofactor in the transport and metabolism of long-chain fatty acids. 60

In treatment of acute VPA toxicity, including coma, L-carnitine's mechanism of action is hypothesized to derive from its ability to decrease elevated ammonia levels. Carnitine coadministration may counterbalance adverse drug effects of extended AED therapy, but such benefit may vary depending on the agent(s) being used, dosing and duration of therapy, patient age and health status, initial carnitine balance, and other factors.

Research

The body of evidence investigating interactions between anticonvulsant medications and carnitine is strong and largely consistent in its findings, but conclusive assessment of clinical implications is difficult because of significant limitations in the research. Carnitine depletion characterizes most of the medications in this drug class, or at least many of the patients. However, many studies failed to assess carnitine status before initiation of anticonvulsant therapy. Broader evidence suggests that individuals prescribed these medications may already be at higher risk for preexisting compromised carnitine status. 1,61

Valproic acid causes carnitine deficiency, notably in infants and children with epilepsy. Prolonged treatment with VPA, more than other anticonvulsants, enhances renal losses of carnitine esters, lowers serum carnitine levels, and results in secondary carnitine deficiency. In most cases these decreased carnitine levels have no obvious pathological significance, and most children manifest no symptoms of carnitine deficiency. However, anticonvulsant-induced depletion may occasionally cause symptoms of carnitine deficiency such as severe cardiac dysfunction. Typical adverse effects reported in patients treated with VPA include anemia, fatigue, hyperammonemia, hypotonia, lethargy, unexplained stupor, and carnitine-responsive cardiomyopathy. Recurrent episodes of a Reye's-like syndrome with low concentrations of carnitine in liver and muscle, reduced plasma glucose levels, and ketone bodies are among the most serious consequences of carnitine depletion. 62 Coulter 63 hypothesized in a 1984 letter that carnitine depletion plays a central role in VPA's hepatotoxicity. Dreifuss and Langer 62 proposed that the risk of AED-related liver damage increases in children under 24 months of age. Melegh and Trombitas 64 described lipid globule accumulation with ultrastructural abnormalities of mitochondria in the skeletal muscle of seven children treated with VPA. They attributed these lipid deposits to inhibited mitochondrial fatty acid oxidation, a carnitine-dependent process.

Several preliminary studies and controlled trials have demonstrated dramatic reductions in serum carnitine levels and related adverse effects associated with anticonvulsant medications, especially among pediatric patients receiving multidrug therapy. Morita et al. 65 measured decreases in the serum concentrations of total and free carnitine in patients who had received multiple doses of AEDs, especially those receiving sodium valproate, but also those receiving other medications. Nevertheless, no abnormal losses of carnitine in urine were observed. Several factors that may be relevant to the hypocarnitinemia were surveyed statistically. Further analysis revealed that in all the patients, levels of total carnitine and free carnitine were inversely correlated with the dosages of sodium valproate, and that dosage of sodium valproate was the most critical negative contributor to carnitine status. Furthermore, these researchers found that poor muscle volume and coadministration of phenytoin with sodium valproate enhanced hypocarnitinemia. Rodriguez-Segade et al. 66 conducted a study with 183 adult outpatients and 49 controls in which 77% of subjects taking VPA demonstrated a deficiency of free carnitine (i.e., >2 SD below the mean). In contrast, such deficiency was observed in 27% of subjects receiving combined phenytoin-phenobarbital therapy, 23% taking carbamazepine, and 16% receiving phenytoin monotherapy.

In a clinical trial involving 37 children, Zelnick et al. 67 assessed blood carnitine levels before and after therapy using several different anticonvulsant medications. They found that carnitine levels decreased significantly from baseline values only in children receiving VPA; total blood carnitine dropped from 45.3 µM before treatment to 34.9 µM after treatment among those subjects. In contrast, total blood carnitine dropped from 45.7 µM pretreatment to 43.4 µM posttreatment among subjects administered carbamazepine and from 44.9 µM pretreatment to 42.1 µM posttreatment among subjects in the phenobarbital group. 68 Castro-Gago et al. 68 measured serum carnitine levels in 32 epileptic children before and during treatment with VPA, carbamazepine, and phenobarbital. They found that both free-carnitine and total-carnitine levels declined significantly with respect to pretreatment levels in all three treated groups. Levels dropped most markedly and consistently in the VPA-treated group, 35% of whom exhibited carnitine deficiency (i.e., total carnitine <30 µmol/L) by the twelfth month of treatment. In none of the three groups were serum carnitine levels significantly correlated with the serum concentration of the anticonvulsant drug. Based on these findings, the authors recommended that physicians prescribing any of these drugs to children monitor their serum carnitine levels.

In contrast, Hug et al. 69 studied 471 children of various ages on eight variations of AED monotherapy and polytherapy (with 32 healthy controls, age 1 to 16 years). They found that phenobarbital monotherapy more significantly reduced carnitine levels than VPA monotherapy. “Only for phenobarbital was there an inverse correlation between the serum concentration of the drug and that of carnitine concentration.” Total carnitine and free carnitine were deficient in the following percentages of patients receiving AED monotherapy: phenobarbital (36% total; 21% free), VPA (23% total; 9% free), phenytoin (12% total; 8% free), and carbamazepine (8% total; 1% free). For patients receiving AED polytherapy, the percentages were VPA-carbamazepine (44% total; 22% free), phenobarbital-phenytoin (37% total; 16% free), phenobarbital-carbamazepine (18% total; 6% free). Although both Zelnick et al. 67 and Castro-Gago et al. 68 reported decreased serum carnitine levels among individuals using VPA, Zelnick found no such association for phenobarbital, but Castro-Gago found such an effect. Subsequently, Verotti et al. 70 questioned whether the depletion of carnitine and the increase in blood ammonia levels (both caused by VPA) are actually related to each other. Their investigation found that the depletion of carnitine was significantly more severe when epileptic individuals were taking VPA together with other antiseizure medications.

The risk of carnitine depletion and drug-induced deficiency may reflect the disease severity, broader health condition, and nutritional status of patients being treated with anticonvulsants more than the adverse effects of the medications themselves. De Vivo et al. 71 reviewed many clinical trials demonstrating an association between anticonvulsant therapy and decreased carnitine levels, especially in children and particularly involving VPA. They concluded that younger children (1-10 years) treated with VPA tend to demonstrate a more significant decrease in carnitine concentrations than older children (10-18 years) and advised L-carnitine coadministration in certain cases, particularly infants and young children (especially those <2 years) diagnosed with neurological disorders and receiving VPA and multiple anticonvulsants. Earlier, Van Wouwe 1 had noted that before VPA therapy, plasma free-carnitine values were age dependent and increased during childhood. Hirose et al. 72 conducted a randomized, case-control study involving 45 children with epilepsy, age 6 to 21 years, who were treated with VPA monotherapy and were free of abnormal neurological findings or nutritional problems; an age-matched group of 45 children without epilepsy served as the control group. Although serum VPA concentration exhibited a weak negative correlation with both total and free serum carnitine, there was no significant difference in total and free serum carnitine levels between the VPA-treated and control groups; plasma ammonia levels were the same in the two groups. These researchers concluded that children on a regular diet receive sufficient carnitine intake to adequately meet their daily carnitine requirement, that valproate therapy does not deplete carnitine levels in otherwise healthy children, and that VPA-induced carnitine deficiency is not likely to occur in this population.

Hiraoka et al. 73 studied the pharmacokinetics of decreases in the blood free-carnitine level as an adverse effect of VPA administered to epileptic patients in connection with changes in the VPA disposition. They observed that serum free-carnitine level in patients taking at least one of phenobarbital, phenytoin, and carbamazepine in addition to VPA was significantly lower than that in the group given only these other agents without VPA. Subjects medicated only with VPA also tended to have a lower serum free-carnitine level than controls, although not to a significant degree. Among all the patients taking VPA with or without other AED(s), a significantly positive correlation was observed between the serum free-carnitine level and the value of dose and level ratio (L/D) of VPA. Such findings indicate that both the serum free-carnitine concentration and the L/D value of VPA were remarkably reduced in patients receiving both VPA and another AED. The researchers interpreted these results to suggest that enzyme induction by and accelerated hepatic degradation of VPA plays a role in the reduction of free carnitine levels, which is then reflected in free-carnitine deficiency.

Plasma carnitine levels are often low in people taking VPA for extended periods. Coadministration of carnitine may normalize low carnitine levels associated with anticonvulsant therapy, especially children taking VPA. Even so, concomitant carnitine therapy for patients undergoing long-term AED therapy remains contentious, and research findings have yet to evolve to an established level of consistency, refinement, and clarity to form a consensus or enable formulation of well-founded clinical algorithms. Ohtani et al. 74 compared plasma carnitine and blood ammonia concentrations in 25 severely handicapped patients, age 3 to 21 years, with those of 27 age-matched control subjects. Of the handicapped patients, 14 were treated with anticonvulsant drugs, including VPA; the remaining 11 patients were treated with drugs other than VPA. They found that plasma carnitine concentrations were lower and blood ammonia values were higher in VPA-treated patients than in the untreated patients and control subjects, and that plasma carnitine concentrations exhibited a significant inverse relationship with both VPA dosage and blood ammonia values. Both carnitine deficiency and hyperammonemia were corrected after oral administration of DL-carnitine (50 mg/kg/day) for 4 weeks.

Ater 60 reported that carnitine appeared to be protective against the drug-induced liver damage for which children treated with anticonvulsants are at high risk. Subsequently, Freeman et al. 75 conducted a placebo-controlled, double-blind, crossover study involving 47 children with seizures being treated with either VPA or carbamazepine that attempted to assess changes in “well-being,” as perceived by parents, after oral carnitine coadministration (100 mg/kg). They found that well-being scores improved weekly for all children (i.e., when either placebo or carnitine was administered), and that none of the analyses of improved well-being achieved statistical significance. These researchers concluded that available evidence indicated that prophylactic coadministration of carnitine to children taking anticonvulsant medications for alleviating common, nonspecific symptoms was not warranted. Furthermore, they noted that, as of 1994, there were no reliable clinical or laboratory tests for determining symptomatic carnitine deficiency caused by anticonvulsant administration, and that further research was needed to develop methods for identifying children in need of carnitine coadministration.

Melegh, Pap, et al. 76 compared 10 randomly selected subjects with age- and gender-matched controls in a randomized trial measuring energy metabolism in children receiving long-term VPA therapy. Eight of the treated subjects showed an altered fuel consumption pattern, including a significant reduction in the amount of fats oxidized and a shift to increased utilization of carbohydrates. Carnitine coadministration for a month (50 mg/kg/day as oral solution, divided equally into two or three doses) reversed this pattern as the respiratory quotient decreased, oxidation of fats increased, and consumption of carbohydrates decreased. Van Wouwe 1 demonstrated that “prolonged” VPA treatment results in secondary carnitine deficiency in children. He compared samples of plasma drawn at the onset of and after 9 months of continuous VPA treatment in 13 children and found that mean plasma free carnitine decreased by 40%, plasma total carnitine decreased by 20%, and the esterified/free-carnitine ratio increased by 40%. Biochemical evidence of carnitine deficiency appeared in 6 of the 13 subjects, although clinical symptoms, primarily fatigue and excessive sleepiness, were observed in only two. The author concluded that a “dose of 15 mg/kg body weight is effective to reverse the clinical symptoms of carnitine deficiency within a week” and advised carnitine coadministration in children complaining of fatigue during prolonged VPA therapy. He also noted that the “dose to prevent deficiency is not yet established.” Gidal et al. 77 found that carnitine (50 mg/kg) protected children from valproate-induced, transient hyperammonemia.

Carnitine therapy may do more than only protect against AED-induced depletion and resulting adverse effects. Research by Sakemi and Takada 78 indicates that concomitant administration of L-carnitine during VPA therapy may potentiate the activity of VPA. They reported that L-carnitine coadministration increased carnitine concentrations significantly in serum and liver but not in the brain, and that the resultant increase of serum free-VPA concentrations by concomitant carnitine apparently caused free-VPA concentrations in the brain to increase. Overall, the research literature reveals an understanding that carnitine has an effect on the performance and toxicity of VPA, but no clear agreement as to a potential therapeutic role for carnitine has emerged.

Currently available clinical trials exhibit mixed and conflicting results and cast doubt on the efficacy of carnitine administration as a generic prescription for individuals taking AEDs. However, no clinical trial has yet addressed the issues of carnitine depletion and carnitine administration over an extended time. These medications are often prescribed for years or decades, and the risk of cumulative depletion patterns and their clinical implications have yet to be adequately addressed. Long-term, well-designed clinical trials are warranted to investigate the adverse effects on carnitine level and function and compensatory concomitant carnitine administration, particularly with reference to specific age groups, contextual pathological and nutritional status, and various anticonvulsant agents. Adequate tools for assessing carnitine status are critical to accurate and clinically applicable findings.

Apart from issues of chronic depletion and corrective replacement therapy, intravenous (IV) carnitine is among the interventions used in acute VPA-induced hepatotoxicity and overdose; high-flux hemodialysis and charcoal hemoperfusion are also used in such situations. 79

Reports

Several case reports have described VPA-related carnitine deficiency causing abdominal pain in children. For example, Shuper et al. 79 reported on a pediatric patient with intractable epilepsy who had a complete remission of severe VPA-induced abdominal pain immediately after administration of L-carnitine, 300 mg/day.

Houghton and Bowers 80 reported a case of VPA overdose in a woman with polysubstance overdose and a history of alcoholism and hepatitis B and C. Several interventions were necessary to address the multiple toxicities involved and the sequence of risk and immediacy. L-Carnitine at 100 mg/kg/day was administered to correct hyperammonemia and encephalopathy and continued until serum ammonia and VPA levels had normalized.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In consideration of research available at this time, physicians prescribing valproic acid, phenobarbital, or related anticonvulsant medications may find it prudent to coadminister oral L-carnitine prophylactically or monitor carnitine blood levels and coadminister L-carnitine as indicated. Susceptibility to adverse effects appears to be greater in three groups: infants and young children receiving VPA, patients receiving anticonvulsant polytherapy (especially those <2 years), and individuals with severe neurological conditions, compromised nutritional status, or other medical conditions characterized by compromised liver function or systemic overload. Concurrent treatment with pivalate prodrugs is contraindicated because of increased urinary carnitine excretion. Although higher-dose carnitine (3-7 g/day) likely would prevent deficiency, there is little clinical experience in this area and no available clinical research to serve as a guideline. Serum carnitine levels should be monitored during long-term anticonvulsant therapy. Concomitant administration of L-carnitine may be advisable for some patients. Nevertheless, clinically significant deficiencies of carnitine appear to be uncommon, and no conclusive evidence has confirmed that most individuals benefit from carnitine supplements.

In 1998, a panel of pediatric neurologists and experts on L-carnitine coadministration strongly recommended oral L-carnitine for all infants and children taking VPA, as well as for adults with carnitine deficiency syndromes, people with VPA-induced hepatic and renal toxicity, people on kidney dialysis, and premature infants on TPN. Oral carnitine in three to four divided doses totaling 100 mg/kg, up to a maximum of 2 g/day, represents a consensus dosage level. However, physicians prescribing anticonvulsant medications should advise patients to refrain from starting any supplemental use of carnitine outside the context of regular supervision and close monitoring by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.

In acute VPA toxicity, use of IV L-carnitine remains investigational but can be considered in patients with coma, central nervous system (CNS) depression, evidence of hepatic dysfunction, and hyperammonemia. In such patients, L-carnitine may be initiated at 50 to 100 mg/kg/day (up to maximum dose of 2 g/day) to correct hyperammonemia and encephalopathy. Such therapy would be continued until serum ammonia and VPA levels had normalized.

Zidovudine (AZT) and Related Antiretroviral Agents, Reverse-Transcriptase Inhibitor (Nucleoside)
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Calcium Channel Blockers
Cisplatin, Ifosfamide, and Related Chemotherapy
Gentamicin
Propranolol and Related Beta-1-Adrenoceptor Antagonists (Beta-1-Adrenergic Blocking Agents)
nutrient-nutrient interactions
Alpha-Lipoic Acid
Coenzyme Q10, Fish Oil, Magnesium, and Taurine
herb-nutrient interactions
Hawthorn
Citations and Reference Literature
  • 1.Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Int J Vitam Nutr Res 1995;65:211-214.
  • 2.Lamhonwah AM, Tein I. Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene. Biochem Biophys Res Commun 1998;252:396-401.View Abstract
  • 3.DiPalma JR. Carnitine deficiency. Am Fam Physician 1988;38:243-251.View Abstract
  • 4.Stumpf DA, Parker WD Jr, Angelini C. Carnitine deficiency, organic acidemias, and Reye’s syndrome. Neurology 1985;35:1041-1045.
  • 5.Del Favero A. Carnitine and gangliosides. Lancet 1988;2:337.View Abstract
  • 6.Tamamogullari N, Silig Y, Icagasioglu S, Atalay A. Carnitine deficiency in diabetes mellitus complications. J Diabetes Complications 1999;13:251-253.View Abstract
  • 7.Van Oudheusden LJ, Scholte HR. Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2002;67:33-38.View Abstract
  • 8.Rai G, Wright G, Scott L et al. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer’s dementia. Curr Med Res Opin 1990;11:638-647.
  • 9.Benvenga S, Lakshmanan M, Trimarchi F. Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. Thyroid 2000;10:1043-1050.View Abstract
  • 10.Benvenga S, Ruggeri RM, Russo A et al. Usefulness of l-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 2001;86:3579-3594.View Abstract
  • 11.Bartels GL, Remme WJ, den Hartog FR et al. Additional antiischemic effects of long-term l-propionylcarnitine in anginal patients treated with conventional antianginal therapy. Cardiovasc Drugs Ther 1995;9:749-753.View Abstract
  • 12.Tepaske R, Velthuis H, Oudemans-van Straaten HM et al. Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial. Lancet 2001;358:696-701.View Abstract
  • 13.Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 2003;18:61-71.
  • 14.Castro-Gago M, Lojo S, Novo I et al. Effects of chronic allopurinol therapy on purine metabolism in Duchenne muscular dystrophy. Biochem Biophys Res Commun 1987;147:152-157.View Abstract
  • 15.Borum PR, Broquist HP, Roelops RJ. Muscle carnitine levels in neuromuscular disease. J Neurol Sci 1977;34:279-286.View Abstract
  • 16.Camina F, Novo-Rodriguez MI, Rodriguez-Segade S, Castro-Gago M. Purine and carnitine metabolism in muscle of patients with Duchenne muscular dystrophy. Clin Chim Acta 1995;243:151-164.View Abstract
  • 17.Willner JH, Ginsburg S, Dimauro S. Active transport of carnitine into skeletal muscle. Neurology 1978;28:721-724.View Abstract
  • 18.Rebouche CJ, Engel AG. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes: evidence for alterations in tissue carnitine transport. J Clin Invest 1984;73:857-867.View Abstract
  • 19.Abdel-aleem S, el-Merzabani MM, Sayed-Ahmed M et al. Acute and chronic effects of Adriamycin on fatty acid oxidation in isolated cardiac myocytes. J Mol Cell Cardiol 1997;29:789-797.View Abstract
  • 20.Mortensen SA, Olsen HS, Baandrup U. Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br Heart J 1986;55:274-282.View Abstract
  • 21.Mortensen SA, Aabo K, Jonsson T, Baandrup U. Clinical and non-invasive assessment of anthracycline cardiotoxicity: perspectives on myocardial protection. Int J Clin Pharmacol Res 1986;6:137-150.View Abstract
  • 22.Steinherz LJ, Steinherz PG, Tan CT et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991;266:1672-1677.View Abstract
  • 23.McFalls EO, Paulson DJ, Gilbert EF, Shug AL. Carnitine protection against Adriamycin-induced cardiomyopathy in rats. Life Sci 1986;38:497-505.View Abstract
  • 24.Neri B, Cini-Neri G, Bartalucci S, Bandinelli M. Protective effect of l-carnitine on cardiac metabolic damage induced by doxorubicin in vitro. Anticancer Res 1986;6:659-662.View Abstract
  • 25.Neri B, Neri GC, Bandinelli M. Differences between carnitine derivatives and coenzyme Q10 in preventing in vitro doxorubicin-related cardiac damages. Oncology 1988;45:242-246.
  • 26.Alberts DS, Peng YM, Moon TE, Bressler R. Carnitine prevention of Adriamycin toxicity in mice. Biomedicine 1978;29:265-268.View Abstract
  • 27.Maccari F, Ramacci MT. Antagonism of doxorubicin cardiotoxicity by carnitine is specific of the l-diasteroisomer. Biomedicine 1981;35:65-67.View Abstract
  • 28.Sayed-Ahmed MM, Salman TM, Gaballah HE et al. Propionyl-l-carnitine as protector against Adriamycin-induced cardiomyopathy. Pharmacol Res 2001;43:513-520.View Abstract
  • 29.Mijares A, Lopez JR. l-Carnitine prevents increase in diastolic [Ca2+] induced by doxorubicin in cardiac cells. Eur J Pharmacol 2001;425:117-120.View Abstract
  • 30.Brouwer CA, Gietema JA, van den Berg MP et al. Long-term cardiac follow-up in survivors of a malignant bone tumour. Ann Oncol 2006;17:1586-1591.View Abstract
  • 31.De Leonardis V, Neri B, Bacalli S, Cinelli P. Reduction of cardiac toxicity of anthracyclines by l-carnitine: preliminary overview of clinical data. Int J Clin Pharmacol Res 1985;5:137-142.View Abstract
  • 32.Chavez GA, Hernandez IM, Ollarve CF, Natera YM. Myocardial protection by l-carnitine in children treated with Adriamycin. Rev Lat Cardiol 1997;18:208-214.
  • 33.Marsden JR, Trinick TR, Laker MF, Shuster S. Effects of isotretinoin on serum lipids and lipoproteins, liver and thyroid function. Clin Chim Acta 1984;143:243-251.View Abstract
  • 34.Laker MF, Green C, Bhuiyan AK, Shuster S. Isotretinoin and serum lipids: studies on fatty acid, apolipoprotein and intermediary metabolism. Br J Dermatol 1987;117:203-206.View Abstract
  • 35.Kim JY, Lee JJ, Kim KS. Acetyl-CoA carboxylase beta expression mediated by MyoD and muscle regulatory factor 4 is differentially affected by retinoic acid receptor and retinoid X receptor. Exp Mol Med 2003;35:23-29.View Abstract
  • 36.Georgala S, Schulpis KH, Georgala C, Michas T. l-Carnitine supplementation in patients with cystic acne on isotretinoin therapy. J Eur Acad Dermatol Venereol 1999;13:205-209.View Abstract
  • 37.Famularo G, Matricardi F, Nucera E et al. Carnitine deficiency: primary and secondary syndromes. In: De Simone C, Famularo G, eds. Carnitine Today. Austin, Texas: RG Landes; 1997.
  • 38.Galland S, Georges B, Le Borgne F et al. Thyroid hormone controls carnitine status through modifications of gamma-butyrobetaine hydroxylase activity and gene expression. Cell Mol Life Sci 2002;59:540-545.View Abstract
  • 39.DeFelice SL, Gilgore SG. The antagonistic effect of carnitine in hyperthyroidism: preliminary report. J New Drugs 1966;6:351-353.View Abstract
  • 40.Benvenga S, Lapa D, Cannavo S, Trimarchi F. Successive thyroid storms treated with l-carnitine and low doses of methimazole. Am J Med 2003;115:417-418.View Abstract
  • 41.DeFelice SL, Kohl, H. Carnitine Defense: a Nutraceutical Formula to Prevent and Treat Heart Disease. Emmaus, Pa: Rodale Press; 1999.
  • 42.Garzya G, Amico RM. Comparative study on the activity of racemic and laevorotatory carnitine in stable angina pectoris. Int J Tissue Reactions 1980;2:175-180.
  • 43.Tishkin VS, Dunaev VV, Kryzhanovskii SA et al. [Study of anti-ischemic action of carnitine chloride and its effects on the effectiveness of antianginal agents]. Kardiologiia 1990;30:89-91.View Abstract
  • 44.McCarty MF. Management of acute myocardial infarction with natural physiological agents. Med Hypotheses 1983;11:449-465.View Abstract
  • 45.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.View Abstract
  • 46.Inoue N, Hirata K, Akita H, Yokoyama M. Palmitoyl-l-carnitine modifies the function of vascular endothelium. Cardiovasc Res 1994;28:129-134.View Abstract
  • 47.Brass EP. Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol Rev 2002;54:589-598.View Abstract
  • 48.Holme E, Greter J, Jacobson CE et al. Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 1989;2:469-473.View Abstract
  • 49.Diep QN, Bohmer T, Storrosten OT et al. [Slow replenishment of carnitine level after long-term treatment with pivampicillin/pivmecillinam]. Tidsskr Nor Laegeforen 1994;114:1614-1616.View Abstract
  • 50.Melegh B, Sumegi B, Sherry AD. Preferential elimination of pivalate with supplemental carnitine via formation of pivaloylcarnitine in man. Xenobiotica 1993;23:1255-1261.View Abstract
  • 51.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.View Abstract
  • 52.Abrahamsson K, Eriksson BO, Holme E et al. Pivalic acid–induced carnitine deficiency and physical exercise in humans. Metabolism 1996;45:1501-1507.View Abstract
  • 53.Holme E, Jodal U, Linstedt S, Nordin I. Effects of pivalic acid–containing prodrugs on carnitine homeostasis and on response to fasting in children. Scand J Clin Lab Invest 1992;52:361-372.View Abstract
  • 54.Kahn J, Lagakos S, Wulfsohn M et al. Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial. JAMA 1999;282:2305-2312.View Abstract
  • 55.Sirtori CR, Calabresi L, Ferrara S et al. l-Carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutr Metab Cardiovasc Dis 2000;10:247-251.View Abstract
  • 56.Brescia F, Balestra E, Iasella MG, Damato AB. Effects of combined treatment with simvastatin and l-carnitine on triglyceride levels in diabetic patients with hyperlipidaemia. Clin Drug Invest 2002;22:23-28.
  • 57.Derosa G, Cicero AF, Gaddi A et al. The effect of l-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clin Ther 2003;25:1429-1439.View Abstract
  • 58.Solfrizzi V, Capurso C, Colacicco AM et al. Efficacy and tolerability of combined treatment with l-Carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus. Atherosclerosis 2006;188:455-461.View Abstract
  • 59.Burns MJ, Palmer BF. Valproic acid intoxication. In: Rose BD, ed. UpToDate. Wellesley, Mass: UpToDate; 2001.
  • 60.Ater SB. A developmental center population treated with VPA and l-carnitine. Update 1993: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.
  • 61.Chung S, Choi J, Hyun T et al. Alterations in the carnitine metabolism in epileptic children treated with valproic acid. J Korean Med Sci 1997;12:553-558.View Abstract
  • 62.Dreifuss FE, Langer DH. Hepatic considerations in the use of antiepileptic drugs. Epilepsia 1987;28 Suppl 2:S23-S29.View Abstract
  • 63.Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet 1984;1:689.View Abstract
  • 64.Melegh B, Trombitas K. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics 1997;28:257-261.View Abstract
  • 65.Morita J, Yuge K, Yoshino M. Hypocarnitinemia in the handicapped individuals who receive a polypharmacy of antiepileptic drugs. Neuropediatrics 1986;17:203-205.View Abstract
  • 66.Rodriguez-Segade S, de la Pena CA, Tutor JC et al. Carnitine deficiency associated with anticonvulsant therapy. Clin Chim Acta 1989;181:175-181.View Abstract
  • 67.Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence? Acta Paediatr 1995;84:93-95.
  • 68.Castro-Gago M, Eiris-Punal J, Novo-Rodriguez MI et al. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13:546-549.
  • 69.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.
  • 70.Verrotti A, Greco R, Morgese G, Chiarelli F. Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs. Int J Clin Lab Res 1999;29:36-40.
  • 71.De Vivo DC, Bohan TP, Coulter DL et al. l-Carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998;39:1216-1225.View Abstract
  • 72.Hirose S, Mitsudome A, Yasumoto S et al. Valproate therapy does not deplete carnitine levels in otherwise healthy children. Pediatrics 1998;101:E9.
  • 73.Hiraoka A, Arato T, Tominaga I. Reduction in blood free carnitine levels in association with changes in sodium valproate (VPA) disposition in epileptic patients treated with VPA and other anti-epileptic drugs. Biol Pharm Bull 1997;20:91-93.View Abstract
  • 74.Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr 1982;101:782-785.View Abstract
  • 75.Freeman JM, Vining EP, Cost S, Singhi P. Does carnitine administration improve the symptoms attributed to anticonvulsant medications? A double-blinded, crossover study. Pediatrics 1994;93:893-895.
  • 76.Melegh B, Pap M, Morava E et al. Carnitine-dependent changes of metabolic fuel consumption during long-term treatment with valproic acid. J Pediatr 1994;125:317-321.
  • 77.Gidal BE, Inglese CM, Meyer JF et al. Diet- and valproate-induced transient hyperammonemia: effect of l-carnitine. Pediatr Neurol 1997;16:301-305.View Abstract
  • 78.Sakemi K, Takada G. Effect of carnitine on valproic acid concentrations in serum, brain, and liver. Pediatr Neurol 1998;18:331-333.View Abstract
  • 79.Shuper A, Gutman A, Mimouni M. Intractable epilepsy. Lancet 1999;353:1238.View Abstract
  • 80.Houghton BL, Bowers JB. Valproic acid overdose: a case report and review of therapy. MedGenMed 2003;5:5.View Abstract
  • 81.Dalakas MC, Leon-Monzon ME, Bernardini I et al. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol 1994;35:482-487.View Abstract
  • 82.Famularo G, De Simone C, Tzantzoglou S, Trinchieri V. Apoptosis, anti-apoptotic compounds and TNF-alpha release. Immunol Today 1994;15:495-496.View Abstract
  • 83.Campos Y, Arenas J. Muscle carnitine deficiency associated with zidovudine-induced mitochondrial myopathy. Ann Neurol 1994;36:680-681.View Abstract
  • 84.Semino-Mora MC, Leon-Monzon ME, Dalakas MC. The effect of l-carnitine on the AZT-induced destruction of human myotubes. Part II. Treatment with l-carnitine improves the AZT-induced changes and prevents further destruction. Lab Invest 1994;71:773-781.View Abstract
  • 85.Walker UA. Update on mitochondrial toxicity: where are we now? J HIV Ther 2003;8:32-35.
  • 86.De Simone C, Famularo G, Tzantzoglou S et al. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral l-carnitine. AIDS 1994;8:655-660.View Abstract
  • 87.Rossi L, Serafini S, Schiavano GF et al. Metabolism, mitochondrial uptake and toxicity of 2′,3′-dideoxycytidine. Biochem J 1999;344 Pt 3:915-920.View Abstract
  • 88.Moretti S, Famularo G, Marcellini S et al. l-Carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002;4:391-403.View Abstract
  • 89.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.View Abstract
  • 90.Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today 1997;18:44-51.View Abstract
  • 91.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.View Abstract
  • 92.Graziano F, Bisonni R, Catalano V et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002;86:1854-1857.View Abstract
  • 93.Kalinec GM, Fernandez-Zapico ME, Urrutia R et al. Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss. Proc Natl Acad Sci USA 2005;102:16019-16024.View Abstract
  • 94.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.View Abstract
  • 95.Hagen TM, Liu J, Lykkesfeldt J et al. Feeding acetyl-l-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 2002;99:1870-1875.
  • .[No authors listed.] [The National Board of Health and Welfare’s warning: antibiotics containing pivalin acid cause carnitine deficiency.] Lakartidningen 1990;87(30-31):2436. [Swedish]
  • .[No authors listed.] [Antibiotics containing pivalic acid and carnitine deficiency: a report of the present status: therapeutic recommendations.] Lakartidningen 1991;88(30-31):2543. [Swedish]
  • .Abdel-Aziz MT, Abdou MS, Soliman K, et al. Effect of carnitine on blood lipid pattern in diabetic patients. Nutr Rep Int 1984;29:1071-1079.
  • .Alesci S, De Martino MU, Mirani M, et al. L-carnitine: A nutritional modulator of glucocorticoid receptor functions. FASEB J 2003;17(11):1553-1555.
  • .Anand I, Chandrashenkhan Y, De Giuli F, et al. Acute and chronic effect of propionyl-L-carnitine on the hemodynamics, exercise capacity and hormones of patients with congestive heart failure. Cardiovasc Drugs Ther 1998;12:291-299.
  • .Barker GA, Green S, Askew CD, et al. Effect of propionyl-L-carnitine on exercise performance in peripheral arterial disease. Med Sci Sports Exerc 2001;33(9):1415-1422.
  • .Bartel LL, Hussey JL, Shrago E. Effect of dialysis on serum carnitine, free fatty acids, and triglyceride levels in man and the rat. Metabolism 1982;31(9):944-947.
  • .Bartels GL, Remme WJ, Holwerda KJ, et al. Anti-ischaemic efficacy of L-propionylcarnitine: a promising novel metabolic approach to ischaemia? Eur Heart J 1996;17(3):414-420.
  • .Bartels GL, Remme WJ, Pillay M, et al. Acute improvement of cardiac function with intravenous L-propionylcarnitine in humans. J Cardiovasc Pharmacol 1992;20(1):157-164.
  • .Bartels GL, Remme WJ, Pillay M, et al. Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol 1994;74(2):125-130.
  • .Beers MH, Berkow R, eds. The Merck manual of diagnosis and therapy. 17th ed. Whitehouse Station, NJ: Merck and Co, Inc; 1999, 881-883.
  • .Bella R, Biondi R, Raffaele R, et al. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 1990;10(6):355-360.
  • .Bertorini TE, Palmieri GM, Griffin J, et al. Chronic allopurinol and adenine therapy in Duchenne muscular dystrophy: effects on muscle function, nucleotide degradation, and muscle ATP and ADP content. Neurology 1985;35(1):61-65.
  • .Beversdorf D, Allen C, Nordgren R. Valproate induced encephalopathy treated with carnitine in an adult. J Neurol Neurosurg Psychiatry 1996;61(2):211.
  • .Biagiotti G, Cavallini G. Acetyl-L-carnitine vs tamoxifen in the oral therapy of Peyronie’s disease: a preliminary report. BJU Int 2001;88(1):63-67.
  • .Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-carnitine in Alzheimer’s disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin 2003;19(4):350-353.
  • .Bohles H, Lehnert W. The effect of intravenous L-carnitine on propionic acid excretion in acute propionic acidaemia. Eur J Pediatr 1984;143(1):61-63.
  • .Bohmer T, Endresen L. [Pivampicillin (Pondocillin) and pivmecillinam (Selexid) can result in carnitine deficiency.] Tidsskr Nor Laegeforen 1990;110(16):2090-2091. [Norwegian] (Review)
  • .Bolognesi M, Amodio P, Merkel C, et al. Effect of 8-day therapy with propionyl-L-carnitine on muscular and subcutaneous blood flow of the lower limbs in patients with peripheral arterial disease. Clin Physiol 1995;15(5): 417-423.
  • .Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. Int J Clin Pharmacol Ther Toxicol 1986;24:511-516.
  • .Bordin D, Bottecchia D, Bettini V, et al. Effect of middle-intensity exercise on carnitine and beta-hydroxybutyrate plasmatic concentration in men and women. J Sports Med Phys Fitness 1992;32(4):394-399.
  • .Bratton SL, Garden AL, Bohan TP, et al. A child with valproic acid-associated carnitine deficiency and carnitine-responsive cardiac dysfunction. J Child Neurol 1992;7(4):413-416.
  • .Brevetti G, Attisano T, Perna S, et al. Effect of L-carnitine on the reactive hyperemia in patients affected by peripheral vascular disease: a double-blind, crossover study. Angiology 1989;40:857-862.
  • .Brevetti G, Perna S, Sabba C, et al. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26(6):1411-1416.
  • .Brevetti G, Chiariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988;77(4):767-773.
  • .Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol 1999;34(5):1618-1624.
  • .Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcarnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J 1992;13(2):251-255.
  • .Brooks JO III, Yesavage JA, Carta A, et al. Acetyl L-carnitine slows decline in younger patients with Alzheimer’s disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr 1998;10(2):193-203.
  • .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(4):225-235.
  • .Calabrese V, Scapagnini G, Catalano C, et al. Effects of acetyl-L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat. Neurochem Res 2001;26(2):167-174.
  • .Calvani M, Carta A, Caruso G, et al. Action of acetyl-L-carnitine in neurodegeneration and Alzheimer’s disease. Ann N Y Acad Sci 1992;663:483-486.
  • .Camina MF, Rozas I, Gomez M, et al. Short-term effects of administration of anticonvulsant drugs on free carnitine and acylcarnitine in mouse serum and tissues. Br J Pharmacol 1991;103:1179-1183.
  • .Campaniello E, Petrarolo N, Meriggiola MC, et al. Carnitine administration in asthenospermia. The 4th International Congress of Andrology. Florence, Italy, May 14, 1989.
  • .Campi N, Todeschini GP, Scarzella L. Selegiline versus L-acetylcarnitine in the treatment of Alzheimer-type dementia. Clin Ther 1990;12(4):306-314.
  • .Campistol J, Chavez B, Vilaseca MA, et al. [Antiepileptic drugs and carnitine.] Rev Neurol 2000;30(Suppl 1):S105-S109. [Spanish]
  • .Capecchi PL, Laghi Pasini F, Quartarolo E, et al. Carnitines increase plasma levels of adenosine and ATP in humans. Vasc Med 1997;2(2):77-81.
  • .Caponnetto S, Canale C, Masperone MA, et al. Efficacy of L-propionylcarnitine treatment in patients with left ventricular dysfunction. Eur Heart J 1994;15:1267-1273.
  • .Castiglione A, Cornelio F, Vendemia F, et al. [Acute recurrent renal insufficiency in a patient with atraumatic rhabdomyolysis caused by carnitine-palmitoyltransferase deficiency.] Minerva Nefrol 1981;28(3):229-234. [Italian]
  • .Castro-Gago M, Camina F, Rodriguez-Segade S. Carnitine deficiency caused by valproic acid. J Pediatr 1992;120(3):496. (Letter)
  • .Cavallini G, Biagiotti G, Koverech A, et al. Oral propionyl-l-carnitine and intraplaque verapamil in the therapy of advanced and resistant Peyronie’s disease. BJU Int 2002;89:895-900.
  • .Cavallini G, Caracciolo S, Vitali G, et al. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology 2004;63(4):641-646.
  • .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.
  • .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(2):146-153.
  • .Cipolli C, Chiari G. Effects of L-acetylcarnitine on mental deterioration in the aged: initial results. Clin Ter 1990;132:479-510. [Italian; English abstract]
  • .Columbani P, Wenk C, Kunz I, et al. Effect 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.
  • .Costa M, Canale D, Filicori M, et al. L-carnitine in idiopathic asthenozoospermia: a multicenter study: Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26(3):155-159.
  • .Coulter DL. Carnitine deficiency in epilepsy: risk factors and treatment. J Child Neurol 1995;10(Suppl 2):S32-S39.
  • .Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol 1991;6(1):7-14. (Review)
  • .Dal Lago A, De Martini D, Flore R, et al. Effects of propionyl-L-carnitine on peripheral arterial obliterative disease of the lower limbs: a double-blind clinical trial. Drugs Exp Clin Res 1999;25(1):29-36.
  • .Dal Negro R, Pomari G, Zoccatelli O, et al. L-carnitine and rehabilitative respiratory physiokinesitherapy: metabolic and ventilatory response in chronic respiratory insufficiency. Int J Clin Pharmacol Ther Toxicol 1986;24:453-456.
  • .Dal Negro R, Turco P, Pomari C, et al. Effects of L-carnitine on physical performance in chronic respiratory insufficiency. Int J Clin Pharmacol 1988;26:269-272.
  • .Dal Negro R, Zoccatelli D, Pomari C, et al. L-carnitine and physiokinesiotherapy in chronic respiratory insufficiency: preliminary results. Clin Trials J 1985;22:353-360.
  • .Dal Negro R, Turco P, Pomari C, et al. Effects of L-carnitine on physical performance in chronic respiratory insufficiency. Int J Clin Pharmacol Ther Toxicol 1988;26:269-272.
  • .Davini P, Bigalli A, Lamanna F, et al. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18(8):355-365.
  • .Dean SM. Pharmacologic treatment for intermittent claudication. Vasc Med 2002;7(4):301-309. (Review)
  • .Deckert J. Propionyl-L-carnitine for intermittent claudication. J Fam Pract 1997;44(6):533-534.
  • .Del Favero A. Carnitine and gangliosides. Lancet 1988;2:337. (Letter)
  • .De Simone C, Famularo G, eds. Carnitine today. Austin, TX: RG Landes; 1997.
  • .Diep QN, Bohmer T, Holme JI, et al. Slow replenishment of carnitine deficiency after cessation of long-term treatment with pivaloyl-containing antibiotics. Pharm World Sci 1993;15(5):225-259.
  • .Diep QN, Brors O, Bohmer T. Formation of pivaloylcarnitine in isolated rat heart cells. Biochim Biophys Acta 1995;1259(2):161-165.
  • .Diep QN, Bohmer T, Schjerven L. Reduced carnitine and ketogenesis in the pivampicillin treated rat. Biochem Pharmacol 1992;44(6):1226-1228.
  • .Digiesi V, Palchetti R, Cantini F. The benefits of L-carnitine in essential arterial hypertension. Minerva Med 1989;80:227-231.
  • .Di Marzio L, Alesse E, Roncaioli P, et al. Influence of L-carnitine on CD95 cross-lining-induced apoptosis and ceramide generation in human cell lines: correlation with its effects on purified acidic and neutral sphingomyelinases in vitro. Proc Assoc Am Physicians 1997;109(2):154-163.
  • .Di Marzio L, Moretti S, D’Alo S, et al Acetyl-L-carnitine administration increases insulin-like growth factor 1 levels in asymptomatic HIV-1-infected subjects: correlation with its suppressive effect on lymphocyte apoptosis and ceramide generation. Clin Immunol 1999;92(1):103-110.
  • .Dipalma JR. Carnitine deficiency. Am Fam Physician 1988;38:243-251.
  • .Duncker DJ, Sassen LM, Bartels GL, et al. L-propionylcarnitine does not affect myocardial metabolic or functional response to chronotropic and inotropic stimulation after repetitive ischemia in anesthetized pigs. J Cardiovasc Pharmacol 1993;22(3):488-498.
  • .Engel AG, Bancker BQ, Eiben RM. Carnitine deficiency: clinical morphological and biochemical observations in a fatal-case. J Neurol Neurosurg Psychiatry 1977;40:313.
  • .Famularo G, Moretti S, Marcellini S, et al. Cellular dysmetabolism: the dark side of HIV-1 infection. J Clin Lab Immunol 1996;48(3):123-132. (Review)
  • .Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 1997;11(2):185-190.
  • .Ferraresi R, Troiano L, Roat E, et al. Protective effect of acetyl-l-carnitine against oxidative stress induced by antiretroviral drugs. FEBS Lett 2006;580(28-29):6612-6616.
  • .Fosslien E. Review: mitochondrial medicine: cardiomyopathy caused by defective oxidative phosphorylation. Ann Clin Lab Sci 2003;33(4):371-395. (Review)
  • .Fugh-Berman A. Herbs and dietary supplements in the prevention and treatment of cardiovascular disease. Prev Cardiol 2000;3(1):24-32. (Review)
  • .Garzya G, Corallo D, Fiore A, et al. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res 1990;16:101-106.
  • .Garzya G, Amico RM. Comparative study on the activity of racemic and laevorotatory carnitine in stable angina pectoris. Int J Tissue Reactions 1980;2:175-180.
  • .Giamberardino MA, Dragani L, Valente R, et al. Effects of prolonged L-carnitine administration on delayed muscle pain and CK release after eccentric effort. Int J Sports Med 1996;17(5):320-324.
  • .Ghidini O, Azzurro M, Vita G, et al. Evaluation of the therapeutic efficacy of L-carnitine in congestive heart failure. Int J Clin Pharmacol Ther Toxicol 1988;26(4):217-220. Erratum in Int J Clin Pharmacol Ther Toxicol 1989;27(8):418.
  • .Giamberardino MA, Dragani L, Valente R, et al. Effects of prolonged L-carnitine administration on delayed muscle pain and CK release after eccentric effort. Int J Sports Med 1996;17:320-324.
  • .Gidal BE, Inglese CM, Meyer JF, et al. Diet-and valproate-induced transient hyperammonemia: effect of L-carnitine. Pediatr Neurol 1997;16(4):301-305.
  • .Giovannini M, Agostoni C, Salari PC. Is carnitine essential in children? J Int Med Res 1991;19:88-102.
  • .Greco AV, Mingrone G, Bianchi M, et al. Effect of propionyl-L-carnitine in the treatment of diabetic angiopathy: controlled double-blind trial versus placebo. Drugs Exp Clin Res 1992;18(2):69-80.
  • .Green RE, Levine AM, Gunning MJ. The effect of L-carnitine supplementation on lean body mass in male amateur body builders. J Am Diet Assoc 1997;(Suppl):A-72.
  • .Heinonen OJ. Carnitine and physical exercise. Sports Med 1996;22(2):109-132.
  • .Hiatt WR, Regensteiner JG, Creager MA, et al. Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Am J Med 2001;110(8):616-622.
  • .Iliceto S, Scrutinio D, Bruzzi P, et al. Effect 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.
  • .Iyer R, Gupta A, Khan A, et al. Does left ventricular function improve with L-carnitine after acute myocardial infarction? J Postgrad Med 1999;45:38-41.
  • .Iyer RN, Khan AA, Gupta A, et al. L-carnitine moderately improves the exercise tolerance in chronic stable angina. J Assoc Physicians India 2000;48(11):1050-1052.
  • .Kelly GS. Insulin resistance: lifestyle and nutritional interventions. Altern Med Rev 2000;5(2):109-132. (Review)
  • .Kelley RI. The role of carnitine supplementation in valproic acid therapy. Pediatr 1994;93(6 Pt 1):891-892. (Editorial)
  • .Kendler BS. Carnitine: an overview of its role in preventive medicine. Prev Med 1986;15:373-390. (Review)
  • .Kerns W II, Kline J, Ford MD. Blocker and calcium channel blocker toxicity. Emerg Med Clin North Am 1994;12:2:365-390.
  • .Kobayashi A, Masumura Y, Yamazaki N. L-carnitine treatment for congestive heart failure: experimental and clinical study. Jpn Circ J 1992;56:86-94.
  • .Kraemer WJ, Volek JS, French DN, et al. The effects of L-carnitine L-tartrate supplementation on hormonal responses to resistance exercise and recovery. J Strength Cond Res 2003;17(3):455-462.
  • .Lagioia R, Scrutinio D, Mangini SG, et al. Propionyl-L-carnitine: a new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol 1992;34:167-172.
  • .Larsen H, Nielsen GL, Sorensen HT, et al. A follow-up study of birth outcome in users of pivampicillin during pregnancy. Acta Obstet Gynecol Scand 2000;79(5):379-83.
  • .Lefkowitz RJ, Hoffman BB, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman & Gilman’s the pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill; 1996:105-139.
  • .Lenzi A, Lombardo F, Sgro P, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril 2003;79:292-300.
  • .Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A 2002;99(4):2356-2361.
  • .Loster H, Miehe K, Punzel M, et al. Prolonged oral L-carnitine substitution increases bicycle ergometer performance in patients with severe, ischemically induced cardiac insufficiency. Cardiovasc Drugs Ther 1999;13:537-546.
  • .Loumbakis P, Anezinis P, Evangeliou A, et al. Effect of L-carnitine in patients with asthenospermia. Eur Urol 1996;30(Suppl 2):255. (Abstract)
  • .Lowitt S, et al. Acetyl-L-carnitine corrects the altered peripheral nerve function of experimental diabetes. Metabolism 1995;44(5):677-680.
  • .Mancini M, Rengo F, Lingetti M, et al. Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure. Arzneimittelforschung 1992;42:1101-1104.
  • .Mangano NG, Clementi G, Costantino G, et al. Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats. Drugs Exp Clin Res 2000;26(1):7-12.
  • .Marz R. Medical nutrition from Marz. 2nd ed. Portland, OR: Omni Press; 1997.
  • .Matsuda I, Ohtani Y. Carnitine status in Reye and Reye-like syndromes. Pediatr Neurol 1986;2:90-94.
  • .Mazzocchio R, Schieppati M, Scarpini C, et al. Enhancement of recurrent inhibition by intravenous administration of L-acetylcarnitine in spastic patients. J Neurol Neurosurg Psychiatry 1990;53(4):321-326.
  • .McCarty MF. Management of acute myocardial infarction with natural physiological agents. Med Hypotheses 1983;11(4):449-465. (Review)
  • .Melegh B. Carnitine supplementation in pivampicillin treatment. Lancet 1989;2(8671):1096.
  • .Melegh B, Jaszai V. Carnitine content of red blood cells of human subjects treated with pivampicillin and carnitine. Acta Paediatr Hung 1991;31(2):255-261.
  • .Melegh B, Kerner J, Bieber LL. Pivampicillin-promoted excretion of pivaloylcarnitine in humans. Biochem Pharmacol 1987;36(20):3405-3409.
  • .Melegh B, Kerner J, Jaszai V, et al. Differential excretion of xenobiotic acyl-esters of carnitine due to administration of pivampicillin and valproate. Biochem Med Metab Biol 1990;43(1):30-38.
  • .Melegh B, Pap M, Bock I, et al. Relationship of carnitine and carnitine precursors lysine, epsilon-N-trimethyllysine, and gamma-butyrobetaine in drug-induced carnitine depletion. Pediatr Res 1993;34(4):460-464.
  • .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(10):795-799.
  • .Mitchell ME. Carnitine metabolism in human subjects: I: normal metabolism. Am J Clin Nutr 1978;31(2):293-306. (Review)
  • .Mitchell ME. Carnitine metabolism in human subjects: II: values of carnitine in biological fluids and tissues of "normal" subjects. Am J Clin Nutr 1978;31(3):481-491. (Review)
  • .Mitchell ME. Carnitine metabolism in human subjects: III: metabolism in disease. Am J Clin Nutr 1978;31(4):645-659. (Review)
  • .Micic S, Lalic N, Nale DJ, et al. Effects of L-carnitine on sperm motility and number in infertile men. Fertil Steril 1998;70(3 Suppl 1):S12. (Abstract)
  • .Mingrone G, Greco AV, Capristo E, et al. L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 1999;18(1):77-82.
  • .Moncada ML, Vicari E, Cimino C, et al. Effect of acetylcarnitine treatment in oligoasthenospermic patients. Acta Eur Fertil 1992;23:221-224.
  • .Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 2003;18(2):61-71.
  • .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(10):3817-3824.
  • .Moretti S, Famularo G, Marcellini S, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002;4(3):391-403.
  • .Muller-Tyl E, Lohninger A, Fischl F, et al. The effect of carnitine on sperm count and sperm motility. Fertilitat 1988;4:1-4. [German]
  • .Murakami K, Sugimoto T, Woo M, et al. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia 1996;37(7):687-689.
  • .Murray MT. The many benefits of carnitine. Am J Natural Med 1996;3:6-14. (Review)
  • .Navarro-Quesada FJ, Lluch-Fernandez MD, Vaquero-Abellan M, et al. [Evaluation of the effect of long term valproic acid treatment on plasma levels of carnitine, ammonia and amino acids related to the urea cycle in pediatric epileptic patients.] Rev Neurol 1997;25(143):1037-1044. [Spanish]
  • .Obici S, Feng Z, Arduini A, et al. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 2003;9(6):756-761.
  • .Orzali A, Maetzke G, Donzelli F, et al. Effect of carnitine on lipid metabolism in the neonate: II: carnitine addition to lipid infusion during prolonged total parenteral nutrition. J Pediatr 1984;104(3):436-440.
  • .Paradies G, Ruggiero FM, Petrosillo G, et al. Carnitine-acylcarnitine translocase activity in cardiac mitochondria from aged rats: the effect of acetyl-L-carnitine. Mech Ageing Dev 1995;84(2):103-112.
  • .Passeri M, Cucinotta D, Bonati PA, et al. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res 1990;10:75-79.
  • .Pepine CJ. The therapeutic potential of carnitine in cardiovascular disorders. Clin Ther 1991;13(1):2-21; discussion 1. (Review)
  • .Pistorio E, D’Amico G, Pistorio A. [L-carnitine deficiency.] Clin Ter 1996;147(7-8):403-405. [Italian]
  • .Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of chronic fatigue syndrome. Neuropsychobiology 1997;35:16-23.
  • .Prasad K. Homocysteine, a risk factor for cardiovascular disease. Int J Angiol 1999 Jan;8(1):76-86.
  • .Pucciarelli G, Mastursi M, Latte S, et al. The clinical and hemodynamic effects of propionyl-L-carnitine in the treatment of congestive heart failure. Clin Ter 1992;141:379-384. [Italian; English abstract]
  • .Raby WN. Carnitine for valproic acid-induced hyperammonemia. Am J Psychiatry 1997;154(8):1168-1169.
  • .Rai G, Wright G, Scott L, et al. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer’s dementia. Curr Med Res Opin 1990;11:638-647.
  • .Rebuzzi AG, Schiavoni G, Lanza GA, et al. Rhythm of carnitine levels in serum and urine of normal subjects. Drugs Exp Clin Res 1989;15(1):43-46.
  • .Rose SJ, Stokes TC, Patel S, et al. Carnitine deficiency associated with long-term pivampicillin treatment: the effect of a replacement therapy regime. Postgrad Med J 1992;68(805):932-934.
  • .Rubecz I, Sandor A, Hamar A, et al. Blood levels of total carnitine and lipid utilization with and without carnitine supplementation in newborn infants. Acta Paediatr Hung 1984;25(1-2):165-171.
  • .Sabba C, Berardi E, Antonica G, et al. Comparison between the effect of L-propionylcarnitine, L-acetylcarnitine and nitroglycerin in chronic peripheral arterial disease: a haemodynamic double blind echo-Doppler study. Eur Heart J 1994;15(10):1348-1352.
  • .Sachan DS, Rhew TH, Ruark RA. Ameliorating effects of carnitine and its precursors on alcohol-induced fatty liver. Am J Clin Nutr 1984;39(5):738-744.
  • .Salvioli G, Neri M. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res 1994;20:169-176.
  • .Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer’s disease. Arch Neurol 1992;49:1137-1141.
  • .Sayed-Ahmed MM, Mansour HH, Gharib OA, et al. Acetyl-L-carnitine modulates bleomycin-induced oxidative stress and energy depletion in lung tissues. J Egypt Natl Cancer Inst 2004;16(4):237-243.
  • .Sbriccoli A, Carretta D, Santarelli M, et al. An optimised procedure for prenatal ethanol exposure with determination of its effects on central nervous system connections. Brain Res Brain Res Protoc 1999;3(3):264-269.
  • .Seccombe D, Burget D, Frohlich J, et al. Oral L-carnitine administration after jejunoileal by-pass surgery. Int J Obes 1984;8(5):427-433.
  • .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.
  • .Sorbi S, Forleo P, Fani C, et al. Double-blind, crossover, placebo-controlled clinical trial with L-acetylcarnitine in patients with degenerative cerebellar ataxia. Clin Neuropharmacol 2000;23:114-118.
  • .Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology 1991;41(11):1726-1732.
  • .Stadler DD, Bale JF Jr, Chenard CA, et al. Effect of long-term valproic acid administration on the efficiency of carnitine reabsorption in humans. Metabolism 1999;48(1):74-79.
  • .Starling RD, Costill DL, Fink WJ. Relationships between muscle carnitine, age and oxidative status. Eur J Appl Physiol Occup Physiol 1995;71(2-3):143-146.
  • .Sugiyama N, Morishita H, Nagaya S, et al. Biochemical evidence of carnitine effect on propionate elimination. J Inherited Metab Dis 1984;7(3):137-138.
  • .Swamy-Mruthinti S, Carter AL. Acetyl-L-carnitine decreases glycation of lens proteins: in vitro studies. Exp Eye Res 1999;69(1):109-115.
  • .Tamamogullari N, Silig Y, Icagasioglu S, et al. Carnitine deficiency in diabetes mellitus complications. J Diabetes Complications 1999;13(5-6):251-253.
  • .Tepaske R, Velthuis H, Oudemans-van Straaten HM, et al. Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial. Lancet 2001;358(9283):696-701.
  • .Terranova R, Luca S. [Treatment of chronic arterial occlusive disease of the lower limbs with propionyl-1-carnitine in elderly patients.] Minerva Med 2001;92(1):61-6. [Italian]
  • .Teri L, Gibbons LE, McCurry SM, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA 2003;290:2015-2022.
  • .Thal LJ, Calvani M, Amato A, et al. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 2000;55(6):805-810.
  • .Thal LJ, Carta A, Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurology 1996;47:705-711.
  • .Tishkin VS, Dunaev VV, Kryzhanovskii SA, et al. [Study of anti-ischemic action of carnitine chloride and its effects on the effectiveness of antianginal agents.] Kardiologiia 1990;30(10):89-91. [Russian]
  • .Tolu P, Masi F, Leggio B, et al. Effects of long-term acetyl-L-carnitine administration in rats: I: increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacology 2002;27(3):410-420.
  • .Tomassini V, Pozzilli C, Onesti E, et al. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci 2004;218(1-2):103-108.
  • .Torrioli MG, Vernacotola S, Mariotti P, et al. Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome. Am J Med Genet 1999;87:366-368.
  • .Trappe SW, Costill DL, Goodpaster B, et al. The effects of L-carnitine supplementation on performance during interval swimming. Int J Sports Med 1994;15(4):181-185.
  • .Triggs WJ, Gilmore RL, Millington DS, et al. Valproate-associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure. Int J Clin Pharmacol Ther 1997;35(9):353-356.
  • .Turpeinen AK, Kuikka JT, Vanninen E, et al. Long-term effect of acetyl-L-carnitine on myocardial 123I-MIBG uptake in patients with diabetes. Clin Auton Res 2000;10:13-16.
  • .Van Oudheusden L, Scholte H. Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2002;67:33.
  • .Vecchi GP, Chiari G, Cipolli C, et al. Acetyl-l-carnitine treatment of mental impairment in the elderly: evidence from a multicenter study. Arch Gerontol Geriatr 1991;(Suppl 2):159-168.
  • .Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med 2004;66(2):276-282.
  • .Vicari E. Effectiveness of a short-term anti-oxidative high-dose therapy on IVF program outcome in infertile male patients with previous excessive sperm radical oxygen species production persistent even following antimicrobials administered for epididymitis: preliminary results: in: International Meeting on Infertility and Assisted Reproductive Technology, Porto Cervo, Italy, June 11-14, 1997. Bologna, Italy: Monduzzi Editore SpA; 1997.
  • .Vicari E, Cerri L, Cataldo T, et al. Effectiveness of single and combined antioxidant therapy in patients with astheno-necrozoospermia from non-bacterial epididymitis: effects after acetyl-carnitine or carnitine-acetyl-carnitine. The 12th National Conference, Italian Andrology Association. Copanello (CZ), Italy, Jun 9, 1999.
  • .Vikre-Jorgensen J. [Cardiomyopathy caused by carnitine deficiency.] Ugeskr Laeger 1993;155(42):3390-3392. [Danish]
  • .Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159.
  • .Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Med Sci Sports Exerc 1994;26(9):1122-1129.
  • .Werbach MR. Foundations of nutritional medicine. Tarzana, CA: Third Line Press; 1997. (Review)
  • .Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev 2000;5(2):93-108. (Review)
  • .Weschler A, Aviram M, Levin M, et al. High dose of L-carnitine increases platelet aggregation and plasma triglyceride levels in uremic patients on hemodialysis. Nephron 1984;38(2):120-124.
  • .Willner JH, Ginsburg S, DiMauro S. Active transport of carnitine into skeletal muscle. Neurology 1978;28:721-724.
  • .Winter S, Jue K, Prochazka J, et al. The role of L-carnitine in pediatric cardiomyopathy. J Child Neurol (Canada) 1995;10(Suppl. 2):2S45-2S51.
  • .Wolf LR. Adrenergic blocker toxicity. In: Haddad L, Shannon MW, Winchester JF, eds. Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia: WB Saunders; 1998:1031-1040.
  • .Yesilipek MA, Hazar V, Yegin O. L-Carnitine treatment in beta thalassemia major. Acta Haematol 1998;100:162-163.
  • .Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol 2006;16(4):281-287.