Beneficial or Supportive Interaction, with Professional Management

Consensus

Effect and Mechanism of Action

Carnitine is essential for intramitochondrial metabolism of long-chain fatty acids. Researchers have proposed that Duchenne muscular dystrophy (DMD) involves alterations leading to blockage of the inosine monophosphate (IMP) to adenylsuccinate purine pathway. Allopurinol inhibits xanthine oxidase (thus favoring restoration of IMP synthesis) and slows degradation of purines through its effects on adenosine deaminase and purine nucleotide phosphorylase, two key enzymes. ¹⁴ These effects favor restoration of energy charge and thus of membrane integrity, thereby reducing transmembrane losses of essential metabolites. Coadministration of L-carnitine could theoretically benefit individuals with DMD and enhance therapeutic effects of allopurinol.

Research

Individuals with DMD exhibit severely depressed muscle carnitine levels, i.e., approximately 16.5 times lower than in normal subjects. ¹⁵ Such patients also exhibit severely depressed levels of all adenine and guanine nucleotides and some of their metabolites, and ATP levels are approximately 40 times lower than in normal subjects. ¹⁶ Carnitine deficiency in the muscle of DMD patients may be related to this observed ATP deficiency because muscle cells take up carnitine from the serum by a process of active transport. ^17,18

In the first of several studies, Castro-Gago et al. ¹⁴ found that the activity levels of adenosine deaminase and purine nucleotide phosphorylase were more than double in the serum of untreated DMD patients than in normal patients, thus leading to increased rates of purine catabolism. They reported that allopurinol treatment reduces activities to normal or below-normal levels.

Camina et al. ¹⁶ determined levels of purines, purine metabolites, related enzymes, and carnitine in muscle of eight untreated DMD patients, 12 allopurinol-treated DMD patients, and 12 age-matched controls. Together with several other beneficial changes to IMP and related metabolites, allopurinol restored acylcarnitine to normal levels, resulting in improved muscle strength, and significantly increased free carnitine levels.

Evidence based on clinical trials is lacking thus far to determine whether L-carnitine coadministration might enhance this beneficial effect of allopurinol and at what dosage level, if any, an adverse additive effect might occur.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Health care professionals treating individuals with DMD are advised to discuss the effects of the disease process on carnitine status and its implications for their health. Administration of allopurinol may constitute a valuable component of a comprehensive therapeutic strategy in the treatment of such individuals. Clinical evidence is lacking to confirm whether concomitant use of carnitine might improve efficacy of such an approach. However, available research indicates that carnitine is unlikely to produce any adverse effects and suggests that muscle function and strength in such patients would generally benefit from increased carnitine levels, which are known to result from carnitine administration.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Doxorubicin is a highly effective antineoplastic agent, but cardiotoxicity (acute and chronic) is an adverse effect occurring in up to one third of patients treated after a cumulative dose of 300 mg/m ² and increasing sharply beyond a cumulative dose of 360 mg/m ² . The resultant irreversible and dose-dependent cardiomyopathy limits its clinical usefulness. Research indicates that doxorubicin inhibits fatty acid oxidation in part secondary to inhibition of carnitine palmitoyl transferase 1 (CPT-1) and depletion of L-carnitine, its substrate, in cardiac tissue after acute (in vitro) or chronic (in vivo) administration. L-Carnitine also plays a role in fatty acid oxidation independent of CPT-1 or fatty acid chain length. Acute exposure to doxorubicin can cause a concentration- and time-dependent inhibition of CPT-1-dependent long-chain fatty acid oxidation (i.e., of palmitate). Chronic doxorubicin exposure can inhibit palmitate oxidation as much as 40%. Doxorubicin can also acutely inhibit medium- and short-chain fatty acid oxidation, which is independent of CPT-1. ¹⁹

Cardiotoxicity of anthracycline chemotherapy agents is multifactorial and also involves oxidative stress, in part mediated by an iron-catalyzed Fenton reaction; iron-chelating agents have been shown to decrease doxorubicin cardiac toxicity. Two conditions of cardiotoxicity have been recognized. The first is a dose-independent idiosyncratic phenomenon appearing immediately after anthracycline administration and is based on a pericarditis-myocarditis syndrome in patients without previous cardiac disease. The second condition is dose related and characterized by progressive decline of left ventricular systolic function, as assessed by the ejection fraction on nuclear medicine and echocardiographic studies, which may lead to congestive heart failure (CHF). Diastolic dysfunction may also lead to CHF, with or without concomitant compromise of left ventricular ejection fraction. On pathological examination, progressive anthracycline-related cardiac damage may include restrictive endomyocardial disease, characterized by fibrous thickening of the endomyocardium, and dilated cardiomyopathy, as a result of myocardial fibrosis and hypertrophy of surviving myocytes. Symptoms can appear many years after completion of chemotherapy, although sequential assessment of left ventricular systolic and diastolic function will show compromise long before symptomatic CHF ensues. Risk of anthracycline-induced CHF is increased by radiotherapy fields that involve all or part of the heart. ^20-22

Carnitine is well known for its central roles in fatty acid oxidation, mitochondrial integrity and metabolism, cardiovascular function, and muscle tissue (especially myocardium) metabolism. Its depletion impairs these normal activities, and its presence provides protective effects on these tissues and activities. In particular, acute or chronic administration of L-carnitine may abolish the doxorubicin-induced inhibition of palmitate oxidation and reverse acute inhibition of medium- and short-chain fatty acid oxidation by doxorubicin. ¹⁹

Cardiac toxicity is similar between equipotent doses of doxorubicin and daunorubicin, slightly lower for epirubicin, and only one-sixth that of doxorubicin for equipotent doses of mitoxantrone. Doxil and DaunoXome (liposomal doxorubicin and daunorubicin, respectively) have negligible cardiotoxicity, presumably because of negligible cardiac exposure to the active drug with the pharmacokinetics of the liposome-encapsulated preparation.

Research

A wide range of both in vitro and animal research has demonstrated that L-carnitine can prevent or reduce doxorubicin-related cardiac damage. ^23-25 Alberts et al. ²⁶ reported that carnitine significantly decreased doxorubicin-induced cardiotoxicity at both acute high dose and chronic intermittent low dose without decreasing antitumor activity or increasing bone marrow toxicity, based on a mouse model. The findings of an in vitro experiment conducted by Maccari and Ramacci ²⁷ using rat heart tissue indicate that the L-diastereoisomer of carnitine is specific in its reparatory effect against doxorubicin cardiotoxicity, as indicated by heart rate, coronary flow, and contractile force; they noted that the dextrorotatory form ( D-carnitine) was totally inactive. These authors ascribed this benefit to the “natural role played by this substance in metabolic processes.”

Abdel-aleem et al. ¹⁹ investigated the acute and chronic effects of doxorubicin on fatty acid oxidation in isolated cardiac myocytes. Acute exposure to doxorubicin produced a concentration- and time-dependent inhibition of CPT-1-dependent long-chain fatty acid oxidation of palmitate. Chronic doxorubicin exposure (18 mg/kg) inhibited palmitate oxidation 40% and to a similar extent seen in vitro with 0.5 mM doxorubicin. Conversely, acute or chronic administration of L-carnitine completely abolished the doxorubicin-induced inhibition of palmitate oxidation. Furthermore, medium- and short-chain fatty acid oxidation was also inhibited acutely by doxorubicin and could be reversed by L-carnitine, even though they are independent of CPT-1. Doxorubicin also significantly decreased oxidation of the CPT-1-dependent substrate palmitoyl-CoA by 50% in isolated rat heart mitochondria, but only at concentrations greater than 1 mM, which is higher than clinically relevant doxorubicin concentrations.

Similarly, Sayed-Ahmed et al. ²⁸ reported that propionyl- L-carnitine (PLC) reversed cardiotoxic effects in isolated cardiac myocytes and rat mitochondria perfused with doxorubicin (5 mM) without affecting therapeutic effects. For example, daily administration of PLC to doxorubicin-treated rats resulted in complete reversal of drug-induced increase in cardiac enzymes, except lactate dehydrogenase (LDH), which was only reversed by 66%. In cardiac tissue homogenate, doxorubicin caused a significant 53% increase in malonedialdehyde (MDA), a marker of oxidative stress, and a significant 50% decrease in reduced glutathione (GSH), a fundamental intracellular peptide antioxidant; levels. In contrast, PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to doxorubicin-treated rats completely reversed the increase in MDA and the decrease in GSH induced by doxorubicin to normal levels. Overall, PLC therapy completely protected against doxorubicin-induced inhibition of mitochondrial beta-oxidation of long-chain fatty acids. PLC also exerted or induced a significant antioxidant defense mechanism against doxorubicin-induced lipid peroxidation of cardiac membranes. PLC did not interfere with the antitumor activity of doxorubicin while providing these beneficial effects. ²⁸

Mijares and Lopez ²⁹ determined that acute exposure to doxorubicin impaired intracellular Ca ⁺⁺ handling and induced a concentration-dependent elevation of diastolic calcium concentration ([Ca ⁺⁺ ]) in isolated cardiomyocytes loaded with fura-2/AM (acetoxymethyl ester). These adverse effects were not prevented by pretreatment with L-carnitine. However, L-carnitine at 10 µM concentration in the culture medium of the cardiomyocytes fully inhibited the increase in [Ca ⁺⁺ ] induced by this anthracycline derivative. These results indicate that acute exposure to doxorubicin impairs intracellular Ca ⁺⁺ handling and that L-carnitine exerts a cardioprotective effect, in part by preventing the doxorubicin-induced elevation in diastolic Ca ⁺⁺ concentration.

The cardiotoxicity of doxorubicin can be of rapid onset and endure for decades, often without cardiac complaints. In a longitudinal assessment of cardiac function in 22 patients treated with anthracycline chemotherapy for osteogenic sarcoma or malignant fibrous histiocytoma, Brouwer et al. ³⁰ found systolic dysfunction in more than a quarter of the patients and diastolic dysfunction in almost half after two decades (median, 22 years). Moreover, cardiac dysfunction was progressive, as measured at 9, 14, and 22 years. ³⁰

Although limited by their small size and preliminary character, clinical trials have similarly found beneficial effects from coadministration of carnitine with doxorubicin therapy. De Leonardis et al. ³¹ studied nine patients receiving a cumulative dose (200-490 mg/m ² ) of doxorubicin using creatine kinase levels to evaluate acute cardiotoxicity and electrocardiography and echocardiography to evaluate myocardial contractility for chronic cardiotoxicity. Based on their findings, they proposed “systematic use of L-carnitine as adjuvant therapy … during doxorubicin administration” to be cardioprotective. Subsequently, Chavez et al. ³² reported that the cardiotoxic effects of doxorubicin were not observed in children treated with a combination of doxorubicin (cumulative dose, 30-60 mg/kg) and carnitine (1-2 g/day).

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering doxorubicin therapy are advised to consider pretreatment and concomitant use of L-carnitine as a safe measure with significant probability of preventing or reducing the cardiotoxic effect of this powerful antineoplastic agent. A typical therapeutic dosage of L-carnitine would be in the range of 1 to 3 g daily, given orally in two divided doses commencing before doxorubicin therapy, continued throughout therapy, and for several years after treatment, especially if the cumulative dose of doxorubicin is greater than 360 mg/m ² , if the patient has also received thoracic radiation with exposure of all or part of the cardiac volume, or if sequential assessment of left ventricular ejection fraction and/or diastolic function reveal significant decline from pretreatment values. L-Carnitine is not a potent antioxidant, as is coenzyme Q10 (ubiquinone), another nutrient that helps abrogate doxorubicin cardiotoxicity, but which is controversial because at least some of the antineoplastic effect of doxorubicin may be mediated by free-radical production, which can be inhibited by antioxidants. (See Coenzyme Q10 monograph.) The body of evidence indicates that L-carnitine is essentially nontoxic and unlikely to interfere with the efficacy of chemotherapeutic treatment.

Acute cardiotoxicity can be evaluated by creatine kinase, particularly the cardiac-specific MB isoenzyme. Chronic cardiotoxicity can be monitored using electrocardiography and the left ventricular performance by computed M-mode echocardiography measuring the ejection fraction and by MUGA scan (nuclear medicine technique for measuring cardiac ejection fraction), both of which are reliable and highly sensitive, noninvasive parameters for evaluating myocardial contractility.

Anecdotal clinical experience has indicated that therapeutic benefit in existing doxorubicin-induced cardiomyopathy with clinical CHF can be obtained by therapeutic use of L-carnitine, coenzyme Q10, taurine, magnesium, fish oil, and hawthorn (Crataegus)leaf/flower and berry extracts, at least in some cases. Conventional pharmacological management includes angiotensin-converting enzyme (ACE) inhibitors, diuretics, and sometimes digoxin. Integrative management with these nutrients, botanicals, and pharmaceuticals may be of greatest clinical benefit when applied by individuals experienced both in nutritional and conventional medicine. Randomized controlled clinical trials in this area would be of great interest.

Prevention or Reduction of Drug Adverse Effect

Preliminary to Emerging

Effect and Mechanism of Action

The specific mechanism of action underlying the protective effect of carnitine in relation to retinoids is unknown. The hepatotoxic action of isotretinoin can cause abnormalities in liver function, as well as elevations in serum cholesterol and muscle pain and weakness. ^33,34 The resultant symptoms are similar to the main characteristics of carnitine deficiency (e.g., myalgia, weakness, hypotension). The growing body of scientific knowledge about the role of carnitine in hepatic detoxification functions should lead to a better understanding of the interaction between carnitine and retinoids.

Carnitine is well known for its central role in fatty acid oxidation in mitochondria and L-carnitine, in particular, serving as the substrate of CPT-1. Two major isoforms of acetyl-CoA carboxylase (ACC) are present in mammals. The 275-kDa beta form (ACC-β) is predominantly in heart and skeletal muscle, whereas the 265-kDa alpha form (ACC-α) is the major isoform in lipogenic tissues such as liver and adipose tissue. ACC-β plays a major role in controlling fatty acid oxidation by means of the ability of malonyl-CoA to inhibit CPT-1, a rate-limiting enzyme of fatty acid oxidation in mitochondria. ³⁵

Research

Georgala et al. ³⁶ investigated the use of L-carnitine to reduce the adverse effects of isotretinoin, specifically myalgia; 230 patients with cystic acne were treated with isotretinoin (0.5 mg/kg/24 hours). They divided the patients who reported muscular symptoms into two groups; 20 subjects received L-carnitine (100 mg/kg/24 hours orally), and another 20 received placebo. Among these patients, they noted that carnitine blood levels (both total and free, acylcarnitine) were “remarkably decreased at the onset of their muscular symptoms,” along with “the well known increases of their liver enzymes and lipids.” Furthermore, among those patients receiving isotretinoin but not reporting myalgia, they found that laboratory tests showed elevated liver enzymes and lipids along with a decrease in blood carnitine levels and a “remarkable increase” of urinary carnitine excretion. Subjects receiving concomitant L-carnitine, without isotretinoin discontinuation or reduction, reported the disappearance of their muscular symptoms within 5 to 6 days and exhibited normalization in liver enzymes and carnitine levels at the 45th day of their combined therapy. In contrast, the patients who received placebo along with the isotretinoin continued to report myalgias.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing retinoids are advised to monitor liver enzymes, blood lipids, and carnitine levels and to request that patients report any adverse symptoms characteristic of retinoid toxicity. Prophylactic coadministration of L-carnitine provides a safe protective measure with a reasonable probability of efficacy. A typical therapeutic dosage of L-carnitine would be 1 to 2 g daily, given orally in two divided doses.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Bimodal or Variable Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging to Consensus

Effect and Mechanism of Action

Carnitine may partially block activity of thyroid hormone, at least in part by inhibiting thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. ⁹ Cellular levels of L-carnitine decrease in several diseases, including hyperthyroidism. ³⁷

Thyroid hormone controls carnitine status through modifications of gamma-butyrobetaine hydroxylase activity and gene expression. In particular, thyroid hormones interact with lipid metabolism by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Thyroid hormones also increase carnitine bioavailability. ³⁸

Research

Based on animal experiments and unblinded studies in a few hyperthyroid patients from about 45 years ago, carnitine has been considered a peripheral antagonist of thyroid hormone action, at least in some tissues. More recent research has clarified and expanded scientific knowledge of the physiological properties underlying this interaction. Salvatore Benvenga, MD, and fellow researchers at the University of Messina, School of Medicine, Italy, have conducted extensive research into various aspects of the interaction between carnitine and thyroid hormone.

Data from in vitro experiments by Benvenga et al. ⁹ using three thyroid hormone–responsive cell lines demonstrate that carnitine acts as a peripheral antagonist of thyroid hormone (TH) action, with a site of inhibition at or before the nuclear envelope. These researchers noted: “We are aware of no inhibitor of TH uptake that has such a markedly different effect on the nuclear versus whole-cell uptake.”

In an early uncontrolled study, DeFelice and Gilgore ³⁹ observed clinical amelioration of thyrotoxicosis based on the antagonistic effect of carnitine in hyperthyroidism. In a randomized, double blind, placebo-controlled clinical trial involving 50 women being treated for benign goiter under a fixed, thyroid-stimulating hormone (TSH)–suppressive dose of L-T ⁴ for 6 months, Benvenga et al. ¹⁰ demonstrated that 2 or 4 g/day oral L-carnitine both reversed and prevented symptoms of hyperthyroidism and exerted a beneficial effect on bone mineralization. They also proposed its use in the treatment of thyroid storm. Thus, they concluded that “hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use.”

Report

Benvenga et al. ⁴⁰ published a report describing the case of a hyperthyroid patient taking low doses of a conventional antithyroid drug, methimazole (10-15 mg/day), and L-carnitine (2 g/day in two doses) who survived three successive storms, which were associated with potentially life-threatening precipitating factors (post–influenza myocarditis and thrombophlebitis). They remarked that “although L-carnitine does not prevent relapses of thyrotoxicosis, its use should be considered in thyrotoxic patients when intervening factors may precipitate a thyroid storm.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating patients with hyperthyroidism, endogenous or iatrogenic, are advised to consider administering oral L-carnitine with dosage in the range of 1 to 2 g twice daily. Such administration can reverse carnitine depletion associated with hyperthyroid states and support cardiovascular health, which is often compromised in such cases. Confirmatory clinical trials are lacking, but prudence suggests caution in administration of carnitine to individuals with low or borderline thyroid status. Physicians prescribing thyroid hormone are advised to query patients as to supplement use and counsel avoidance of concomitant carnitine. Regular monitoring is appropriate when both agents are clinically indicated.

	Beneficial or Supportive Interaction, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Preliminary to Emerging

Effect and Mechanism of Action

An additive pharmacological effect, as well as a broader supportive synergy, appears to be involved in the combined use of L-carnitine and glyceryl trinitrate (nitroglycerin), although specific research is lacking as to the mechanism(s) of action. DeFelice and Kohl ⁴¹ have proposed that is one of several possible mechanisms for L-carnitine's benefit in cardiac ischemia and infarction. Nitroglycerin vasodilates, reduces cardiac afterload (i.e., work), and thus increases oxygen availability to ischemic myocardium. Increasing carnitine availability may prevent a limited availability of fatty acids and ketoacids for beta-oxidation and ATP production within cardiac myocytes, which depend exclusively on this fuel source. If nitroglycerin restores oxygen, and carnitine restores fuel, the metabolic processes will function more effectively.

Research

Several clinical trials have demonstrated that carnitine administration contributes to reduced angina symptoms and related cardiac events and decreased usage of antianginal medications, particularly glyceryl trinitrate. Garzya and Amico ⁴² reported that oral L-carnitine, 2 g/day, was associated with reduced anginal attacks and decreased glyceryl trinitrate consumption. In experiments with models of myocardial infarction, Tishkin et al. ⁴³ “established that carnitine chloride reduced the size of an ischemic zone, prevented oxidative metabolism, lowered ATP and creatine phosphate levels, inhibited lactate and free fatty acid accumulation in the ischemic myocardium.” They also found that concomitant administration of carnitine chloride “with nitrong and isoptin increased the anti-ischemic potency of the former.”

In a 1983 review of natural physiological agents in the management of acute myocardial infarction, McCarty ⁴⁴ proposed that carnitine infusion could improve the bioenergetics of ischemic myocardium by relieving inhibition of mitochondrial adenine nucleotide.

Cacciatore et al. ⁴⁵ conducted a randomized controlled trial involving 200 patients, 40 to 65 years of age, with exercise-induced stable angina that investigated the therapeutic effect of L-carnitine (2 g/day) in conjunction with their already-instituted therapy over a 6-month period. Compared with the control group, the patients receiving carnitine demonstrated a significant reduction in the number of premature ventricular contractions at rest, as well as an increased tolerance during ergometric cycle exercise, as demonstrated by an increased maximal cardiac frequency, increased maximal systolic arterial blood pressure, and therefore also increased double cardiac product and reduced ST-segment depression during maximal effort. These changes were accompanied by a reduction in the consumption of cardioactive drugs and improvement in cardiac function and resultant performance, as shown by an increase in the number of patients belonging to class I of the New York Heart Association (NYHA) classification. Furthermore, plasma lipid levels showed improvement laboratory analysis. These researchers concluded that “ L-carnitine undoubtedly represents an interesting therapeutic drug for patients with exercise-induced stable angina.”

In isometric contraction experiments using rabbit thoracic aorta and cultured bovine aortic endothelial cells (BAEC), Inoue et al. ⁴⁶ investigated the effect of palmitoyl- L-carnitine (PLC) on endothelium dependent relaxation. They observed that PLC (1-20 µM) inhibited endothelium-dependent relaxation induced by acetylcholine and substance P in a dose-dependent manner, while having no effect on resting tension and glyceryl trinitrate–induced relaxations. Furthermore, although bradykinin, another endothelium-dependent relaxant, induced a biphasic Ca ⁺⁺ transient in BAEC, pretreatment of these cells with PLC (5-10 µM) inhibited bradykinin-induced Ca ⁺⁺ transients. The authors concluded that the inhibitory effect of PLC on endothelium-dependent relaxation results from the suppression of the intracellular calcium signal transduction in endothelial cells and speculated that PLC “may be an important mediator of the impaired vascular endothelial function in myocardial ischaemia.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating patients with angina are advised to consider administering oral L-carnitine, 1 to 2 g twice daily, in concert with nitroglycerin or related intervention. Although further research through well-designed clinical trials is warranted, the available evidence indicates that the established benefits of carnitine administration on cardiac health, particularly myocardial mitochondrial function, may combine effectively with conventional therapies such as nitroglycerin. Physicians treating patients with angina or related cardiovascular conditions are advised to discuss the potential benefits of carnitine administration and the possible advantages of combining it with their conventional therapies. Nevertheless, even though carnitine is generally considered as essentially nontoxic, regular monitoring is appropriate given the slight (and unproven) risk of an excessive additive response contributing to destabilization.

Coordination of care between health care professionals trained and experienced in both conventional pharmacology and nutritional therapies may provide for the most safe and effective approach to integrative therapeutics. Concomitant use of coenzyme Q10, taurine, magnesium, fish oil, and hawthorn (Crataegus)leaf/flower and berry extracts may also be appropriate in some cases.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Mixed to Emerging

Effect and Mechanism of Action

Pivalate (trimethylacetic acid) is used to generate prodrugs to increase oral bioavailability. After oral administration, all pivalate prodrugs are broken down in the GI tract during absorption and hydrolyzed to pivalic acid and the active agent by nonspecific esterases present in most body tissues. The resultant pivaloyl moiety causes carnitine depletion through the increased urinary excretion of carnitine as pivaloylcarnitine.

After hydrolysis of the prodrug, pivalate (as with other carboxylic acids) can be activated inside cells for further metabolism by acyl-CoA synthases to form pivaloyl-CoA. However, unlike other coenzyme A thioesters, pivaloyl-CoA cannot be oxidized to carbon dioxide in human cells. Consequently, pivaloyl-CoA accumulates in cells and acts as a substrate for a variety of acyl-CoA transferases. The kidneys are primarily responsible for excreting the pivaloyl conjugates that are generated by reactions. Subsequently, the dominant route of pivalate elimination is through formation and urinary excretion of pivaloylcarnitine. This increased carnitine excretion introduces potentially significant risk of perturbing normal cellular function because of the important roles of carnitine in cellular homeostasis. ⁴⁷

Research

The increased carnitine excretion caused by pivalate prodrugs is generally accepted as axiomatic. Carnitine deficiency or inborn errors of metabolism resulting in significant carnitine deficiency are among the standard contraindications for pivalate prodrugs. It is generally agreed that long-term treatment or frequently repeated treatment courses using pivalate prodrugs should be used with caution because of increased excretion of carnitine in urine and a reduction of serum carnitine. Nevertheless, the clinical significance of this interaction, the characteristics of patients at increased risk for depletion and adverse sequelae, and the conditions and factors influencing such effects remain unresolved and occasionally controversial.

The limited duration of therapy using most drugs made with pivalic acid and the availability of carnitine from endogenous synthesis and dietary sources reduce the probability of clinically significant carnitine depletion in most cases. Tissue total carnitine content will only be impacted as the urinary losses are sustained over time, and several months of continued pivalate exposure will usually be necessary to impact the liver carnitine pool significantly and lead to depletion of the large muscle carnitine stores. However, Holme et al. ⁴⁸ note that patients with carnitine deficiency can have serious, even fatal, clinical manifestations and caution that the “risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.”

For example, treatment with pivalic acid–liberating antibiotics (e.g., pivampicillin) for 22 and 30 months in children resulted in total muscle carnitine depletion to 10% of reference values. However, no adverse clinical effects were observed or reported, which could be associated with primary or secondary carnitine deficiency. Serum carnitine was significantly reduced after pivampicillin treatment at the highest recommended doses for 7 to 10 days, but levels returned to the normal range within 2 weeks after discontinuing the medication. Despite these reductions in serum carnitine, total body stores of carnitine were reduced by approximately 10%. Thus, the increased excretion of carnitine associated with the use of pivampicillin and other pivalate prodrugs is considered to be without clinical significance in short-term treatment. The frequency with which adverse effects that could be related to carnitine deficiency occur is similar to that of other antibiotics not liberating pivalic acid. ⁴⁷

A study conducted by Diep et al. ⁴⁹ found that replenishment of carnitine levels using normal dietary sources was slow after long-term treatment with pivalate antibiotics. Long-term treatment with pivampicillin and pivmecillinam for 6 to 24 months in five adults and one child reduced the total serum carnitine concentrations to 3.7 to 14.0 µmol/L (reference value: 25-66 µmol/L). In two cases, muscle carnitine was reduced to 0.3 to 0.7 µmol/g wet weight (reference value: 3-5 µmol/g). All patients reported asthenia and muscle symptoms with weakness and pain. One patient developed signs of carnitine depletion in the liver. Serum carnitine levels recovered slowly after cessation of therapy and reached normal concentrations after 6 to 12 months on a normal diet without carnitine supplement. All symptoms caused by carnitine depletion disappeared after the serum carnitine reached 20 µmol/L.

The effects of pivalic acid on carnitine can adversely impact mitochondrial function and metabolic processes in muscles, lungs, and other tissues. In a preliminary study, researchers observed that carnitine administration was associated with preferential elimination of pivalate through formation of pivaloylcarnitine. ⁵⁰ Subsequently, in a study involving 10 children, Melegh et al. ⁵¹ coadministered carnitine (1 g/day) during the latter 4 days of an 8-day course of pivampicillin. Pivampicillin treatment was associated with formation and urinary excretion of pivaloylcarnitine, and administration of carnitine aided the elimination of pivalate as its carnitine ester. These researchers observed that pivampicillin treatment resulted in inhibited oxidation of fats as metabolic fuel and increased utilization of carbohydrates, but that carnitine partially reversed this drug effect by promoting the elimination of the pivaloyl moiety from the body.

Abrahamsson et al. ⁵² administered pivaloyl-conjugated antibiotics to healthy subjects for 54 days to study the effect of carnitine depletion on physical working capacity. The mean carnitine concentration in serum decreased from 35.0 to 3.5 µmol/L, and in muscle from 10 to 4.3 µmol/g noncollagen protein (NCP). The concentration of 3-hydroxybutyrate in serum slightly increased at submaximal exercise in tests performed before and after 54 days’ administration of the drug, an effect attributed to decreased fatty acid oxidation in the liver. Consumption of muscle glycogen also decreased, suggesting decreased glycolysis in the skeletal muscle. However, the concentration of ATP and creatine phosphate did not significantly decrease during exercise, indicating that adequate energy was available for muscle function. Carnitine depletion appeared to affect cardiac function given observed reductions in the work at maximal oxygen uptake and maximal heart rate. Cardiac muscle is an obligate user of fatty acid beta-oxidation as its fuel source (which requires carnitine for transport), as opposed to skeletal muscle, which stores glycogen for anaerobic glycolysis as its initial fuel source.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In most cases, physicians prescribing pivalate prodrugs for short-term use can safely assume that these medications will not cause clinically significant carnitine depletion. Conventional practice does not recommend either measurement of serum carnitine or concomitant administration of prophylactic carnitine as a general measure for patients prescribed pivalic acid–liberating prodrugs for short-term (acute) use. Almost 1 billion treatment days experience with pivalate prodrugs was accumulated worldwide between 1996 and 2001. Despite such widespread usage, published reports of clinical toxicity have been limited to patients with long-duration treatment.

Coadministration of L-carnitine may be appropriate during treatment with these medications in patients demonstrating or at risk for carnitine deficiency or diagnosed with cardiovascular disease, seizure disorder, or HIV infection. Such protective use is generally considered safe and unlikely to interfere with drug efficacy. If used, administration of at least fourfold molar excess of carnitine (vs. pivalate) is advisable, ⁵³ which in most cases would be adequately provided by 1.5 to 2 g twice daily. Notably, pivalate prodrugs intended for chronic use, such as the antiretroviral adefovir dipivoxil, incorporate carnitine as part of the dosing regimen. ⁵⁴

Several important cautions and contraindications arise from the possible adverse effects of these medications on carnitine status. Pivalate prodrugs should be avoided in patients with known or suspected carnitine deficiency. Prudence suggests that use of pivalate prodrugs be avoided in children less than 3 months of age because endogenous carnitine production may not yet be fully developed during the first months of life. Concurrent treatment with valproic acid is also contraindicated, especially in children. In Sweden, pivampicillin is also contraindicated in patients with very small muscle mass. Selection of alternative pharmacological agents may also be judicious in some cases.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Interventions to reduce lipoprotein(a) [Lp(a)] concentration are important given its atherogenic/prothrombotic properties and associations with both coronary artery and cerebrovascular disease. Statin therapy, as well as fibrates and resins, are generally considered incapable of reducing Lp(a) levels and may in many cases contribute to an increase in Lp(a) levels, even while lowering total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Among conventional pharmaceutical interventions, only nicotinic acid (2-4 g/day) is known to reduce Lp(a). However, L-carnitine can lower plasma Lp(a) levels.

Research

A series of clinical trials conducted by Italian researchers have demonstrated the efficacy of L-carnitine in lowering Lp(a) and a synergistic interaction between L-carnitine and statin therapy in lipid-lowering strategies, especially in individuals with type 2 diabetes. In a double-blind, placebo controlled study, Sirtori et al. ⁵⁵ found that L-carnitine (2 g/day) significantly reduced Lp(a) levels in subjects with hyper-Lp(a) (i.e., serum Lp(a) levels of 40-80 mg/dL). Two years later, in a study involving patients with type 2 diabetes and hyperlipidemia, Brescia et al. ⁵⁶ reported that combined therapy with simvastatin (20 mg/day) and L-carnitine (2 g/day) demonstrated greater lipid-lowering efficacy than simvastatin alone, particularly in lowering triglyceride levels. Subsequently, in a trial involving 94 subjects newly diagnosed with type 2 diabetes mellitus being managed through dietary restriction alone, Derosa et al. ⁵⁷ observed significantly lower plasma Lp(a) levels, compared with placebo, after 3 and 6 months of L-carnitine (2 g/day). Based on these findings, Solfrizzi et al. ⁵⁸ conducted an open, randomized, parallel-group study involving 52 patients with type 2 diabetes mellitus, triglyceride serum levels less than 400 mg/dL (<4.5 mmol/L), and Lp(a) serum levels greater than 20 mg/dL (>0.71 mmol/L). Subjects were randomized into two groups of equal size and administered either simvastatin alone (20 mg/day) or simvastatin plus L-carnitine (2 g/day) orally for 60 days. The investigators reported that “Lp(a) serum levels increase[d] from baseline to 60 days in the simvastatin group alone versus a significant decrease in the combination group.” No differences between the two groups were observed regarding LDL cholesterol, non-HDL cholesterol, and apoB serum levels. The consistent pattern of evidence from these trials indicates that the combination of L-carnitine with statin therapy can enhance therapeutic management of hyperlipidemia, particularly in individuals with type 2 diabetes.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating individuals with hyperlipidemia characterized by elevated Lp(a), particularly the context of type 2 diabetes, are advised to consider a comprehensive approach founded on regular exercise and a healthy diet and combining L-carnitine, as well as fish oil, chromium, and niacin (as inositol hexaniacinate), with conventional lipoid management interventions such as statin therapy. As previously noted, L-carnitine is unlikely to produce any adverse effects on the therapeutic action of a statin drug and may in fact mitigate potential adverse effects on Lp(a) status. Enthusiastic support for improved diet, invigorating exercise, and other healthy lifestyle changes are fundamental to an effective integrative strategy for optimizing healthy function, reversing patterns of dyslipidemia and dysglycemia, and reducing risk of cardiovascular disease.

	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

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.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	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

Emerging to Consensus

Effect and Mechanism of Action

Antiretroviral drugs are well known to cause mitochondrial toxicity, peripheral neuropathy, and other significant adverse effects. L-Carnitine normally plays a major role in the transport of long-chain fatty acids across the inner mitochondrial membrane and facilitates the beta-oxidation of fatty acids.

Reduced levels of carnitine in serum and muscle are found in most patients treated with antiretroviral therapy using AZT and related agents. These agents are well known for causing muscle damage, notably mitochondrial myopathy characterized by depletion of mitochondrial DNA, enzymatic defects in the respiratory chain system, poor utilization of long-chain fatty acids, and accumulation of lipid droplets within the muscle fibers. ^81-84 Thus, reduced muscle carnitine levels, resulting from decreased carnitine uptake by the muscle, are associated with depletion of energy stores within the muscle fibers.

Destructive changes have been observed in other critical sites. Didanosine (ddI), stavudine (d4T), and zalcitabine (ddC) are relatively strong inhibitors of g-polymerase and thus cause a time- and dose-dependent decrease in the intracellular levels of mitochondrial DNA. ⁸⁵ Acetyl-carnitine deficiency and impairment of mitochondrial DNA synthesis are also crucial to the pathogenesis of axonal peripheral neuropathy, a severe dose-limiting toxicity often associated with didanosine, zalcitabine, and stavudine. ^86,87 With regard to zalcitabine (ddC), ddCDP-choline appears to be the zalcitabine metabolite primarily responsible for mitochondrial toxicity. ⁸⁷ Carnitine depletion has also been observed in peripheral blood mononuclear cells (PBMCs) of HIV-infected individuals. ⁸⁸ Disrupted mitochondrial membrane potential (along with increased oxidant stress) also appears in the CD4 and CD8 cells of asymptomatic HIV-infected subjects with advanced immunodeficiency treated with AZT and ddI. ⁸⁴

Coadministration of L-carnitine may restore carnitine levels, correct disrupted mitochondrial transmembrane potential, and decrease apoptotic CD4 and CD8 lymphocytes to support immune function and limit or reverse some of the adverse effects of these medications.

Research

The adverse effects of AZT and related antiretroviral nucleoside analogs, particularly on carnitine levels, have been well established in over a decade of research and clinical observations. Their implications for patient health and therapeutic outcomes have also become increasingly clear.

Several studies published in 1994 focused on carnitine depletion in HIV patients and linked it to the action of antiretroviral nucleoside analogs. In an in vitro study using human muscle tissue, Semino-Mora et al. ⁸⁴ observed depopulation of Leu-19–positive myotubes and destructive changes in mitochondria, including accumulation of lipid droplets, when exposed to AZT at concentrations of 250 µM and higher. Dalakas et al. ⁸¹ examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. They described a pattern of “DNA-depleting mitochondrial myopathy” associated with zidovudine (AZT) use, which is “histologically characterized by the presence of muscle fibers with ‘ragged-red’-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers).” This muscle cell damage caused by AZT results in accumulation of lipid droplets within the muscle fibers from poor utilization of long-chain fatty acids. Reduced muscle carnitine levels, from decreased carnitine uptake by the muscle, are associated with depletion of energy stores within the muscle fibers. De Simone et al. ⁸⁶ reported carnitine depletion in PBMCs of 20 male patients with advanced AIDS and normal serum levels of carnitines. Campos and Arenas ⁸³ also published a letter reporting muscle carnitine deficiency associated with AZT-induced mitochondrial myopathy.

Preliminary but growing evidence indicates that the L-carnitine may mitigate mitochondrial toxicity associated with zidovudine (AZT) and other nucleoside analogs, provide independent therapeutic benefits on HIV infection parameters, and complement conventional chemotherapeutic regimens in HIV-infected patients.

In a randomized, placebo-controlled clinical trial involving 20 male patients with advanced AIDS (stage IV-CI), De Simone et al. ⁸⁶ randomly assigned subjects to receive either oral L-carnitine (6 g/day) or placebo for 2 weeks. AIDS patients exhibited cellular carnitine depletion (with concentrations of total carnitine in PBMCs lower than in healthy controls), even though serum carnitine levels were within normal range. These researchers found that treatment with high-dose L-carnitine was associated with a significant trend toward the restoration of appropriate intracellular carnitine levels and strongly improved proliferative responsiveness by lymphocytes in the S and G ² -M stages to mitogens. They also observed a strong reduction in serum triglycerides in the L-carnitine group at the end of the trial compared with baseline levels, which would be expected from improved efficiency of fatty acid transport and utilization.

In an in vitro experiment using human muscle tissue, Semino-Mora et al. ⁸⁴ found that the addition of L-carnitine (5 mM) to muscle cultures pretreated with AZT (0.0027 to 135 µg/mL) preserves the integrity and volume of mitochondria, prevents AZT-associated destruction of human myotubes, preserves structural integrity and volume of mitochondria, and prevents the accumulation of lipids. ⁸⁹ Such findings suggest that L-carnitine provides independent therapeutic benefit through its effects on immune system function rather than on the pathogen itself. ⁹⁰

Uncontrolled apoptosis plays a critical role in the loss of T lymphocytes in HIV-infected individuals. The Fas/Fas ligand system and ceramide, an endogenous mediator of Fas-triggered apoptosis, appear to be particularly important in the progression of HIV infection. The signal transduced by the Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Disruption of mitochondrial transmembrane potential is an early, irreversible step in the effector phase of apoptosis that allows identification of an additional pool of lymphocytes irreversibly committed to undergo apoptosis, despite still lacking the morphological features typical of apoptosis. Both in vitro and in vivo research show that L-carnitine inhibits Fas-induced apoptosis and ceramide production. ^86,91

Moretti, Alesse, et al. ⁹¹ conducted a series of studies investigating the relationship of carnitine to lymphocyte apoptosis, oxidant stress, and immune function in subjects infected with HIV. In a pilot study, they administered daily infusions of L-carnitine (6 g) for 4 months to 11 asymptomatic HIV-1-infected subjects, who had refused antiretroviral treatment despite experiencing a progressive decline in CD4 counts, and monitored immunological and virological measures (as well as safety) at the start of the treatment and then on days 15, 30, 90, and 150. L-Carnitine administration resulted in an increase in absolute CD4 counts, which was statistically significant on days 90 and 150 ( p= 0.010 and p= 0.019, respectively). They also observed a positive but not significant trend in the change in absolute counts of CD8 lymphocytes and a gradual but strongly significant ( p= 0.001) decrease in the frequency of apoptotic CD4 and CD8 lymphocytes at the end of the study compared to baseline. Cell-associated levels of ceramide also exhibited a strong decline ( p= 0.001) at the end of the study. L-Carnitine also corrected previously disrupted mitochondrial transmembrane potential. No evidence of L-carnitine toxicity was observed, and no dose reductions were necessary. There was no clinically relevant change in HIV-1 viremia.

In a subsequent trial involving 20 asymptomatic HIV-infected subjects with advanced immunodeficiency, Moretti et al. ⁸⁸ compared the effects of either zidovudine (AZT) and didanosine (ddI) or the same regimen plus L-carnitine over 7 months. As previously, they measured immunological and virological parameters at baseline and after 15, 60, 120, and 210 days of treatment. They found significant reductions in apoptotic CD4 and CD8 cells, lymphocytes with disrupted mitochondrial membrane potential, and lymphocytes undergoing oxidant stress in subjects treated with AZT and ddI plus L-carnitine compared with subjects receiving only the antiviral agents. Fas and caspase-1 were downexpressed and p35 overexpressed in lymphocytes from patients of the L-carnitine group. CD4 and CD8 counts and viremia showed no significant difference between the groups. No evidence of toxicity from L-carnitine was recognized. They concluded that coadministration of L-carnitine “is safe and allows apoptosis and oxidant stress to be greatly reduced in lymphocytes from subjects treated with AZT and DDI.”

In an in vitro experiment, Rossi et al. ⁸⁷ investigated mitochondrial toxicity and peripheral neuropathy caused by 2′,3′-dideoxycytidine (ddCyd; zalcitabine). 2′,3′-Dideoxycytidine 5′-diphosphocholine (ddCDP-choline) is among the metabolites of zalcitabine found in a concentration-dependent manner after incubating human cells with the antiretroviral drug. Uptake of ddCDP-choline into mitochondria is more efficient than dideoxyCTP uptake (the triphosphocholine metabolite), suggesting that ddCDP-choline is the metabolite of zalcitabine responsible for mitochondrial toxicity. Furthermore, these researchers reported that, in the cell-free system investigated, 3.0 mM L-carnitine inhibited the uptake of both ddCTP and ddCDP-choline by mitochondria, and when added to U937 cells grown in the presence of 0.25 µM zalcitabine, 3.0 mM L-carnitine partially abrogated the mitochondrial toxicity of zalcitabine.

Nevertheless, in a 2003 review of antiretroviral nucleoside analog reverse-transcriptase inhibitors (NRTIs), Walker ⁸⁵ concluded that “in established mitochondrial toxicity, cessation of the offending NRTI remains the most effective therapeutic intervention because vitamin cocktails and L-carnitine have, at best, only a marginal effect.” He also notes: “Mitochondrial toxicity cannot yet be adequately monitored and predicted.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating HIV-infected individuals may provide therapeutic benefit by administering L-carnitine regardless of whether they are prescribing AZT or other nucleoside analogs concurrently. Findings from clinical trials and related research support the significant probability that concomitant carnitine therapy may enhance immune function, mitigate the pathological process, prevent the development of myotoxicity, and reduce adverse effects of conventional antiviral therapies. A typical therapeutic dosage of L-carnitine would be in the range of 1 to 3 g daily. However, a large proportion of patients may require an initial dosage of up to 6 g daily to restore carnitine levels, especially if they have become depleted by antiviral medications. The body of evidence indicates that L-carnitine is essentially nontoxic and unlikely to interfere with the efficacy of conventional treatment.

Amlodipine (Norvasc); combination drug: amlodipine and benazepril (Lotrel); bepridil (Bapadin, Vascor), diltiazem (Cardizem, Cardizem CD, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiamate, Tiazac), felodipine (Plendil); combination drugs: felodipine and enalapril (Lexxel); felodipine and ramipril (Triapin); gallopamil (D600), isradipine (DynaCirc, DynaCirc CR), lercanidipine (Zanidip), nicardipine (Cardene, Cardene I.V., Cardene SR), nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XL); combination drug: nifedipine and atenolol (Beta-Adalat, Tenif); nimodipine (Nimotop), nisoldipine (Sular), nitrendipine (Cardif, Nitrepin), verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM); combination drug: verapamil and trandolapril (Tarka).

Many studies have demonstrated the value of L-carnitine in the prevention and treatment of cardiovascular disorders. Some clinicians experienced in nutritional therapeutics have suggested that coadministration of carnitine during calcium channel blocker therapy might introduce an additive or synergistic beneficial effect. Evidence from clinical trials is lacking to support this speculation. However, the pharmacological principles underlying this proposal are reasonable and in accordance with known activities and effects of both agents. Research through well-designed clinical trials may be warranted to explore this potential supportive interaction.

Physicians treating individuals with significant risk for or known presence of cardiovascular disease are advised to discuss with their patients the potential benefits of carnitine. L-Carnitine and L-propionyl-carnitine are the forms most often used for prevention and treatment of cardiovascular conditions, with typical therapeutic dosages in the range of 1 to 3 g daily.

Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ).

In a preliminary study involving nonanemic cancer patients, Graziano et al. ⁹² found that concomitant administration of L-carnitine (2 g twice daily) for 7 days relieved chemotherapy-induced fatigue in 90% of subjects who had been treated with cisplatin or ifosfamide. These findings are limited by the lack of a placebo group in the study, which would have enabled accounting for spontaneous resolution of fatigue. Further research through well-designed clinical trials is warranted.

Gentamicin (G-mycin, Garamycin, Jenamicin).

Based on reports that hearing is improved when L-carnitine is administered to infants with neurological disorders, Kalinec et al. ⁹³ investigated the effectiveness of L-carnitine for preventing the ototoxic effects typically associated with gentamicin therapy. They administered L-carnitine, 100 mg/kg/day, to pregnant guinea pigs beginning either 2 weeks before or simultaneously with gentamicin, 100 mg/kg/day for 7 days. Not only did the administration of L-carnitine prevent neonatal mortality, but it also prevented hearing loss associated with the antibiotic. Thus, using auditory brainstem responses, the authors found that the auditory threshold of untreated offspring was 21 dB, compared with 30 db in those treated with gentamicin but that those treated with L-carnitine starting before or at the same time as gentamicin, demonstrated hearing thresholds restored to 23 db and 21 dB, respectively. Furthermore, confocal microscopy and scanning electron microscopy revealed that L-carnitine ameliorated the significant damage of outer hair cells induced by gentamicin. Further study, using cell culture of an auditory cell line highly sensitive to ototoxic drugs and other biochemical testing, indicated that apoptosis was the mechanism by which gentamicin produced its damaging effects, specifically through upregulation of the Harakiri (Hrk) gene, a proapoptotic member of the Bcl-2 family of proteins, mediated by activation of ERK1/2 and inhibition of the JNK pathways. Their findings suggested that L-carnitine exerted its protective action by preventing inhibition of JNK and the consequent upregulation of Hrk, thus blocking cell death. Based on these findings, these investigators have planned a clinical trial to investigate the ability of L-carnitine to prevent gentamicin-induced ototoxicity.

Propranolol and Related Beta-1-Adrenoceptor Antagonists (Beta-1 Adrenergic Blocking Agents). Propranolol (Betachron, Inderal LA, Innopran XL, Inderal) Related: Acebutolol (Sectral), atenolol (Tenormin), atenolol combination drugs: atenolol and chlortalidone (Co- Tendione, Tenoretic), atenolol and nifedipine (Beta-Adalat, Tenif), sotalol (Betapace, Betapace AF, Sorine); betaxolol (Kerlone), bisoprolol (Zebeta), carteolol (cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL); combination drug: metoprolol and hydrochlorothiazide (Lopressor HCT), nadolol (Corgard), nebivolol (Nebilet), oxprenolol (Trasicor), penbutolol (Levatol), pindolol (Visken), propranolol combination drug: propranolol and bendrofluazide (Inderex), timolol (Blocadren)

Many studies have demonstrated the value of L-carnitine in the prevention and treatment of cardiovascular disorders. Ferro et al. ⁹⁴ reported on the case of a 52-year-old man with dilated cardiomyopathy in whom concomitant treatment with L-carnitine and propranolol restored cardiac function, with a 50% reduction in mitral EPSS (E point septal separation), from 20 to 10 mm, and a decrease from 60 to 57 mm in diastolic diameter. These clinicians concluded that their “experience suggests promising benefits in adopting beta blockers combined with L-carnitine therapy in myocardial failure secondary to dilated cardiomyopathy.”

After reviewing the literature on the treatment of hypertrophic cardiomyopathy, Ferro et al. ⁹⁴ also proposed that the protective action of beta-blocking agents against chronic catecholamine stimulation may be enhanced by the combination with L-carnitine. Notably, L-carnitine plays a synergistic role by acting as an important source of energy because of fatty acid oxidation and by avoiding the accumulation of lipids in the blood plasma and myocardium.

Physicians prescribing beta-blocker therapy are advised to discuss with their patients the potential benefits of concomitant carnitine. L-Carnitine and L-propionyl-carnitine are the forms most frequently used for prevention and treatment of cardiovascular conditions, with typical therapeutic dosages in the range of 1 to 3 g per day.

Hagen et al. ⁹⁵ demonstrated improved memory and metabolic function and decreased oxidative stress in old rats fed the combination of acetyl- L-carnitine and lipoic acid.

Carnitine, coenzyme Q10, fish oil, magnesium, and taurine are critical nutrients in maintaining healthy cardiovascular function, muscle, and brain tissue and can play a valuable therapeutic role in the treatment of cardiovascular disease and other conditions and the support of CNS function. Health care professionals trained and experienced in nutritional therapies often use multiple nutrients together. These agents are all considered essentially nontoxic. Clinical trials investigating their synergistic effects are clearly warranted.

Hawthorn, Crataegus laevigata(Poir) DC., Crataegus monogynaJacq. (Lindm.), Crataegus oxyacantha L. (for C. laevigata).

Concomitant administration of carnitine and Crataegusis common practice among health care professionals trained and experienced in the synergistic use of nutrients and herbs in supporting healthy cardiovascular function and treating cardiovascular conditions. Clinical trials investigating the clinical efficacy of combined therapy using these two agents are lacking, as is research into mechanisms underlying interactions between them. Hawthorn is generally considered essentially nontoxic. Clinical trials investigating their synergistic effects are clearly warranted.