What does it do? L-carnitine is needed to release energy from fat. It transports fatty acids into mitochondria, the powerhouses of cells. L-carnitine is made in the body from the amino acids, lysine and methionine. However, in infancy and in situations of high energy needs, such as pregnancy and breast-feeding, the need for L-carnitine can exceed production by the body. Therefore, L-carnitine is considered a conditionally essential nutrient.1
L-carnitines actions appear to be particularly important in the heart. As an example, patients with diabetes and high blood pressure were given 4 grams of L-carnitine per day in an preliminary study.2 After 45 weeks, irregular heartbeat and abnormal heart functioning decreased significantly compared to nonsupplemented patients. For congestive heart failure, much of the research has used a modified form of carnitine called propionyl-L-carnitine (PC). In one double-blind trial, using 500 mg PC per day led to a 26% increase in exercise capacity after six months.3 In other research, patients with congestive heart failure given 1.5 grams PC daily for 15 days had a 21% increase in exercise tolerance and a 45% increase in oxygen consumption.4
Research shows that people who supplement with L-carnitine while engaging in an exercise regimen are less likely to experience muscle soreness.5 However, the belief that carnitine�s effect on energy release will help build muscle or improve athletic performance has, so far, not been supported by most research.6 7 In a double-blind study of trained athletes, supplementation with 2 grams of L-carnitine two hours before and after a 20 km run failed to improve physical performance or exercise recovery.8
However, L-carnitine has been given to people with chronic lung disease in trials investigating how the body responds to exercise.9 10 In these double-blind reports, 2 grams of L-carnitine taken twice per day for two to four, weeks led to positive changes in lung function and metabolism during exercise.
Beta thalassemia major is an inherited, fatal form of anemia commonly seen in people of Mediterranean descent. People with beta thalassemia major invariably require blood transfusions, which can eventually result in iron overload.11 L-carnitine stabilizes red blood cells and supplementation may decrease the need for blood transfusions. In a preliminary study, children with beta thalassemia major who took 100 mg of L-carnitine per 2.2 pounds of body weight per day for three months, had a significantly decreased need for blood transfusions.12
Where is it found? Dairy and red meat contain the greatest amounts of carnitine. Therefore, people who have a limited intake of meat and dairy products tend to have lower L-carnitine intakes.
Who is likely to be deficient? Carnitine deficiencies are rare, even in strict vegetarians, because the body produces carnitine relatively easily.
Rare genetic diseases can cause a carnitine deficiency. Also, deficiencies are occasionally associated with other diseases, such as diabetes and cirrhosis.13 14 Among people with diabetes, carnitine deficiency is more likely to be found in persons experiencing complications of diabetes (such as retinopathy, hyperlipidemia, or neuropathy), suggesting that carnitine deficiency may play a role in the development of these complications.15 A carnitine deficiency can also result from oxygen deprivation which can occur in some heart conditions. In Italy, L-carnitine is prescribed for heart failure, heart arrhythmias, angina, and lack of oxygen to the heart.16
How much is usually taken? Most people do not need carnitine supplements. For therapeutic use, typical amounts are 1-3 grams per day.
It remains unclear whether the propionyl-L-carnitine form of carnitine used in congestive heart failure research has greater benefits than the L-carnitine form, since limited research in both animals and humans with the more common L-carnitine has also shown very promising effects.17
Are there any side effects or interactions? L-carnitine has not been consistently linked with any toxicity.
The body needs lysine, methionine, vitamin C, iron, niacin, and vitamin B6 to produce carnitine.
Are there any drug interactions? Certain medications may interact with L-carnitine. Refer to the drug interactions safety check for a list of those medications.
References:
1. Giovannini M, Agostoni C, Salari PC. Is carnitine essential in children? J Int Med Res 1991;19:88�102.
2. Digiesi V, Palchetti R, Cantini F. The benefits of L-carnitine in essential arterial hypertension. Minerva Med 1989;80:227�31.
3. 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�4.
4. 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�9.
5. 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�4.
6. 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.
7. Murray MT. The many benefits of carnitine. Am J Natural Med 1996;3:6�14 [review].
8. 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�9.
9. Dal Negro R, Pomari G, Zoccatelli O, Turco P. L-carnitine and rehabilitative respiratory physiokinesitherapy: metabolic and ventilatory response in chronic respiratory insufficiency. Int J Clin Pharmacol Ther Toxicol 1986;24:453�6.
10. Dal Negro R, Turco P, Pomari C, De Conti F. Effects of L-carnitine on physical performance in chronic respiratory insufficiency. Int J Clin Pharmacol Ther Toxicol 1988;26:269�72.
11. Beers MH, Berkow R (eds). The Merck Manual of Diagnosis and Therapy, 17th ed. Whitehouse Station, NJ: Merck and Co., Inc, 1999, 881�3.
12. Yesilipek MA, Hazar V, Yegin O. L-Carnitine treatment in beta thalassemia major. Acta Haematol 1998;100:162�3.
13. Dipalma JR. Carnitine deficiency. Am Fam Physician 1988;38:243�51.
14. Kendler BS. Carnitine: an overview of its role in preventive medicine. Prev Med 1986;15:373�90.
15. Tamamogullari N, Silig Y, Icagasioglu S, Atalay A. Carnitine deficiency in diabetes mellitus complications. J Diabetes Complications 1999;13:251�3.
16. Del Favero A. Carnitine and gangliosides. Lancet 1988;2:337 [letter].
17. Kobayashi A, Masumura Y, Yamazaki N. L-carnitine treatment for congestive heart failure�experimental and clinical study. Jpn Circ J 1992;56:86�94.
L-CARNITINE
Vitamins and immunity: II. Influence of L-carnitine on the immune system.
Acta Vitaminol Enzymol (ITALY) 1982, 4 (1-2) p135-40
Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.
Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L- carnitine.
AIDS (UNITED STATES) May 1994, 8 (5) p655-60
OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4- N-trimethyl-am monio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine.
DESIGN: Immunopharmacologic study.
METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation.
RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels.
CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.
Carnitine in human immunodeficiency virus type 1 infection/acquired immune deficiency syndrome.
J Child Neurol (UNITED STATES) Nov 1995, 10 Suppl 2 pS40-4
There is an increasing body of evidence that subgroups of patients infected with human immunodeficiency virus type 1 possess carnitine deficiency. Secondary carnitine deficiencies in these individuals may result from nutritional deficiencies, gastrointestinal disturbances, renal losses, or shifts in metabolic pathways. However, tissue depletion precipitated by drug toxicities, particularly zidovudine, is a major etiology and concern. Carnitine deficiency may impact on energy and lipid metabolism, causing mitochondrial and immune dysfunction. There are convincing laboratory data showing the in vitro ameliorative effects of L-carnitine supplementation of zidovudine-induced myopathies and lymphocyte function. Studies measuring the impact of L-carnitine supplementation on clinical characteristics are ongoing. (50 Refs.)
Utilization of intracellular acylcarnitine pools by mononuclear phagocytes.
Biochim Biophys Acta (NETHERLANDS) Nov 11 1994, 1201 (2) p321-7
Carnitine is essential for the metabolism of long-chain fatty acids and has both direct and indirect roles in the metabolism of short-chain and medium-chain acyl-CoAs. The purpose of this study was to quantitate and identify the individual acylcarnitines that occur in human mononuclear phagocytes (MNP) after activating them with phorbol-12- myristate 13-acetate (PMA). Mononuclear phagocytes were isolated from healthy adults and the levels of free carnitine and individual acylcarnitines were determined in unactivated and activated cells. The degree of activation of MNP was assessed by following hydrogen peroxide production. In unactivated cells, acetyl-L-carnitine represented more than 80% of the total acylcarnitine pool. Small amounts of 3-carbon and 4-carbon acylcarnitines were present, with less than 10% of the carnitine pool being long-chain acylcarnitine. Free carnitine in unactivated cells represented 7% of the total carnitine pool, which remained essentially unchanged in unactivated cells when monitored for a period of 60 min. However, free carnitine rose to more than 50% of the total pool in PMA-activated cells. Similarly, after 1 h of activation, the acetylcarnitine level in activated cells decreased by more than 50%. These data suggest that acetylcarnitine plays a key metabolic role as MNP initiate an immune response. It was further shown that MNP contain both carnitine acetyltransferase and malonyl-CoA-sensitive carnitine palmitoyltransferase in mitochondrial-enriched fractions, as well as in post-mitochondrial supernatant fractions.
High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients.
Immunopharmacol Immunotoxicol (UNITED STATES) Jan 1993, 15 (1) p1-12
Several reports indicate that systemic carnitine deficiency could occur in acquired immunodeficiency disease syndrome (AIDS), and that primary and secondary carnitine deficiency leads to critical metabolic dysfunctions. L-carnitine supplementation to peripheral blood mononuclear cells (PBMCs) of AIDS patients resulted in significant enhancement of the phytohemagglutinin (PHA)- driven proliferative response. High dose L-carnitine administration (6 gr per day for two weeks) to AIDS patients treated with zidovudine also led to increased PBMCs proliferation and reduced blood levels of triglycerides. In addition, a reduction of beta 2- microglobulin serum levels as well as circulating tumor necrosis factor (TNF)-alpha, mostly in patients exhibiting highly elevated levels, were found at the end of the treatment period. Our data suggest that in vivo L- carnitine could prove useful in ameliorating both the immune response and lipid metabolism in patients with AIDS, irrespective of initial serum carnitines levels. The mechanism(s) accounting for the observed results are currently not clear. Further studies are needed to confirm the hypothesis that L-carnitine affects the expression of HIV-induced cytokine.
Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances.
Int J Clin Pharmacol Res (SWITZERLAND) 1990, 10 (1-2) p53-7
Several immune parameters--particularly T-cell dependent immune responses--are altered in aged subjects. To test the hypothesis that they may be the consequence of more general age-related lymphocyte biochemical alterations, and particularly of the energy producing system, the effect of L-carnitine and acetyl-L-carnitine on cell proliferation was studied in peripheral blood lymphocytes from donors of different ages. The results showed that phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was markedly increased in L-carnitine- or acetyl-L-carnitine-preloaded lymphocytes from young and especially from old subjects. Cells from aged subjects considerably improved their defective proliferative capability. Preliminary observations suggest that L- carnitine-preloading also protected peripheral blood lymphocytes from old donors when such cells were exposed to an oxidative stress.
Carnitine deficiency with cardiomyopathy presenting as neonatal hydrops: successful response to carnitine therapy.
J Inherit Metab Dis (NETHERLANDS) 1990, 13 (1) p69-75
A small-for-date infant presented at birth with severe non- immune hydrops, cardiac failure, metabolic acidosis and hypoglycaemia. Ultrasonography disclosed a cardiomyopathy. Initial therapy consisting of artificial ventilation, inotropes and diuretics resulted in partial disappearance of oedema without significant improvement in cardiac function. Episodes of hypoglycaemia recurred despite continuous glucose infusions. Total serum carnitine from cord blood was 1.65 nmoles/ml and was undetectable on day 20. Oral DL-carnitine supplements resulted in normoglycaemia, dramatic improvement in cardiac function and restoration of serum carnitine levels to normal values. The infant was thereafter maintained on carnitine therapy. Follow-up over 1 year showed moderate growth retardation and normal developmental milestones. In order to account for such a severe neonatal presentation of carnitine deficiency, a combination of defective pre- and postnatal carnitine supply with an inborn error of carnitine handling is considered. The present case illustrates the need for evaluation of carnitine status in fetuses and neonates presenting with hydrops associated with cardiac failure.
Influence of L-carnitine on CD95 cross-linking-induced apoptosis and ceramide generation in human cell lines: Correlation with its effects on purified acidic and neutral sphingomyelinases in vitro
Proceedings of the Association of American Physicians (USA), 1997, 109/2 (154-163)
Recently, we examined the effects of a short-term (5-days) intmvenous L- carnitine (6 g/die) treatment on apoptosis of CD4 and CD8 cells from 10 AIDS patients. Without inducing side effects, L-carnitine administration has been shown to induce a potent reduction in the percentage of cells undergoing apoptosis, paralleled by a significant increase of CD4 and CD8 cells. Interestingly, L-carnitine treatment led to a significant reduction of peripheral blood mononuclear cell-associated ceramide (an intracellular messenger for apoptosis) that correlated with the decrease of apoptotic CD4- and CDS-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug for use with AIDS patients. In this article we report the results of in vitro studies performed to better characterize the effects of L- carnitine on cell apoptosis. Previously, a high expression of the Fas (CD95/APO-1)/Fas ligand system in peripheral blood mononuclear cells from HIV-positive individuals has been reported and could be responsible for the observed relevant apoptosis of both infected and uninfected cells. Thus, we investigated the in vitro effects of L-carnitine on CD95 cross-linking- induced apoptosis through an anti- CD95 mAb in Fas-sensitive cell lines (HUT78 and U937). The results strongly support the in vivo observations. Our data indicate that L-carnitine is able to inhibit CD95- induced apoptosis of these cells, most likely by preventing sphingomyelin breakdown and consequent ceramide synthesis. The effect of L-carnitine seems to be specific for acidic sphingomyelinase as shown by experiments performed in vitro and using purified neutral or acidic sphingomyelinases.
Effect of L-carnitine treatment in vivo on apoptosis and ceramide generation in peripheral blood lymphocytes from AIDS patients
Proceedings of the Association of American Physicians (USA), 1997, 109/2 (146-153)
Lymphocyte apoptosis in HIV-infected individuals may play a role in T- cell depletion and therefore favor progression to AIDS. In this study, we examined the effects of a short-term (5-day) intravenous treatment with L- carnitine (6 g/day) on apoptosis of CD4 and CD8 cells from 10 AIDS patients. L-carnitine administration has been shown to induce a strong reduction in the percentage of both CD4 and CD8 cells undergoing apoptosis. Interestingly, the L-carnitine treatment, which did not show relevant side effects in our patients, led to a strong and significant reduction of peripheral blood mononuclear cell-associated ceramide, an intracellular messenger of apoptosis, that positively correlated with the decrease of apoptotic CD4- and CD8-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug in the treatment of AIDS patients.
High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients
IMMUNOPHARMACOL. IMMUNOTOXICOL. (USA), 1993, 15/1 (1-12)
Several reports indicate that systemic carnitine deficiency could occur in acquired immunodeficiency disease syndrome (AIDS), and that primary and secondary carnitine deficiency leads to critical metabolic dysfunctions. L-carnitine supplementation to peripheral blood mononuclear cells (PBMCs) of AIDS patients resulted in significant enhancement of the phytohemagglutinin (PHA)- driven proliferative response. High dose L-carnitine administration (6 gr per day for two weeks) to AIDS patients treated with zidovudine also led to increased PBMCs proliferation and reduced blood levels of triglycerides. In addition, a reduction of beta2- microglobulin serum levels as well as circulating tumor necrosis factor (TNF)-alpha, mostly in patients exhibiting highly elevated levels, were found at the end of the treatment period. Our data suggest that in vivo L- carnitine could prove useful in ameliorating both the immune response and lipid metabolism in patients with AIDS, irrespective of initial serum carnitines levels. The mechanism(s) accounting for the observed results are currently not clear. Further studies are needed to confirm the hypothesis that L-carnitine affects the expression of HIV-induced cytokines.
Effects of L-CARNITINE administration on left ventricular remodeling after acute anterior myocardial infarction
J Am Coll Cardiol (UNITED STATES) Aug 1995, 26 (2) p380-7
OBJECTIVES. This study was performed to evaluate the effects of L-CARNITINE administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction.
BACKGROUND. CARNITINE is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial CARNITINE deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous CARNITINE administration during these events has a beneficial effect on function.
METHODS. The L-CARNITINE Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double- blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or L-CARNITINE (233 patients) within 24 h of onset of chest pain. Placebo or L-CARNITINE was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction.
RESULTS. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L- CARNITINE compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6- and 12-month evaluation was significantly reduced in the L-CARNITINE group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the L-CARNITINE treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients.
CONCLUSIONS. L-CARNITINE treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event.
The myocardial distribution and plasma concentration of CARNITINE in patients with mitral valve disease.
Surg Today (JAPAN) 1994, 24 (4) p313-7
The myocardial distribution and concentration of CARNITINE and its fractions was studied in 11 patients with mitral valve disease not associated with congestive heart failure (CHF). The plasma concentration of CARNITINE was found to be identical to the normal values documented in the literature. The left ventricular papillary muscle had the highest concentrations of total, short-acyl, long-acyl, and free CARNITINE, being significantly higher than those of the right ventricle, while the right atrial appendage had the lowest values of all fractions of CARNITINE. The proportion of long-acyl CARNITINE to total CARNITINE was significantly greater in the left ventricle than in either the right atrium or the atrial septum, and other CARNITINE fractions were identical in all cardiac chambers. Our results suggest that in the compensated heart with mitral valve disease, CARNITINE and its fractions are greatest in the left ventricle in the muscles of all cardiac chambers, and that long-acyl CARNITINE is most likely to be linked to the cardiac muscle demanding a higher cardiac performance.
Myocardial CARNITINE metabolism in congestive heart failure induced by incessant tachycardia.
Basic Res Cardiol (GERMANY) Jul-Aug 1993, 88 (4) 362-70
Persistent tachycardia induces congestive heart failure (CHF), but the mechanism(s) of progressive ventricular dysfunction is (are) unclear. This study was designed to define possible metabolic causes of myocardial dysfunction in rapid ventricular pacing induced CHF. Twelve adult mongrel dogs were paced to 250 beats/min for 19 days. Plasma CARNITINE, norepinephrine and renin were measured at 0, 1, 2, and 3 weeks. Myocardial high energy phosphates, CARNITINE, glycogen, glucose, non-collagenous protein and collagen were measured at 19 days. Cardiac output, arterial pressure and pulmonary wedge pressure, measured at baseline and with CHF, showed a decrease in cardiac output and increase in pulmonary wedge pressure. Neurohumoral activation was evident by progressively increasing plasma norepinephrine and renin activity and depletion of myocardial norepinephrine. Plasma free CARNITINE rose significantly from 12.6 +/- 2.0 control to 28.3 +/- 3.8 nmol/ml at 19 days (p < 0.001), whereas myocardial total CARNITINE was lower in paced than in control dogs (6.0 +/- 1.9 vs. 14.1 +/- 3.5 nmol/mg non- collagenous protein, p < 0.001). Myocardial ATP ATP and ADP were unchanged, while AMP decreased 22%, and creatine phosphate decreased 30% compared to control animals. Myocardial glucose was normal but glycogen was decreased 54% (p < 0.005). The low myocardial CARNITINE and elevated plasma CARNITINE in pacing induced CHF suggests altered CARNITINE transport or membrane integrity.
The clinical and hemodynamic effects of propionyl-L- CARNITINE in the treatment of congestive heart failure
Clin Ter (ITALY) Nov 1992, 141 (11) p379-84
In order to evaluate the clinical and hemodynamic effects of propionyl-L-CARNITINE (PLC) a randomized, double-blind study versus placebo was performed in 50 patients of both sexes, between 48 and 69 years of age, affected by mild- moderate congestive heart failure. All patients participating in said study were on digitalis and diuretic treatment. 25 of these belonged to the control group, while the other 25 were treated with an oral dose of 1 g b.i.d of propionyl-L-CARNITINE. At the end of six months of treatment maximum exercise time on the treadmill increased 11.1% after 90 days and 16.4% after 180 in the group treated with PLC. From a hemodynamic standpoint, after 30, 90 and 180 days the ejection fraction increased by 7.3%, 10.7% and 12.1%. At the same time, moreover, the systemic vascular resistances were reduced by 14.9%, 20% and 20.6%. In the patients treated with placebo, however, the above-mentioned parameters showed no significant variation. Finally, no unexpected events or toxic effects were observed in any of the patients in either group. As a consequence of these results it is possible to affirm that propionyl-L-CARNITINE, due to its clinical and hemodynamic effects, represents a drug of notable therapeutic interest in patients with congestive heart failure, in whom it may be usefully combined with the usual pharmacological therapy.
L-CARNITINE treatment for congestive heart failure experimental and clinical study.
Jpn Circ J (JAPAN) Jan 1992, 56 (1) p86-94
To evaluate the therapeutic efficacy of l-CARNITINE in heart failure, the myocardial CARNITINE levels and the therapeutic efficacy of l-CARNITINE were studied in cardiomyopathic BIO 14.6 hamsters and in patients with chronic congestive heart failure and ischemic heart disease. BIO 14.6 hamsters and patients with heart failure were found to have reduced myocardial free CARNITINE levels (BIO 14.6 vs FI, 287 +/- 26.0 vs 384.8 +/83.8 nmol/g wet weight, p less than 0.05; patients with heart failure vs without heart failure, 412 +/- 142 vs 769 +/- 267 nmol/g p less than 0.01). On the other hand, long- chain acylCARNITINE level was significantly higher in the patients with heart failure (532 +/- 169 vs 317 +/- 72 nmol/g, p less than 0.01). Significant myocardial damage in BIO 14.6 hamsters was prevented by the intraperitoneal administration of l-CARNITINE in the early stage of cardiomyopathy. Similarly, oral administration of l- CARNITINE for 12 weeks significantly improved the exercise tolerance of patients with effort angina. In 9 patients with chronic congestive heart failure, 5 patients (55%) moved to a lower NYHA class and the overall condition was improved in 6 patients (66%) after treatment with l- CARNITINE. L-CARNITINE is capable of reversing the inhibition of adenine nucleotide translocase and thus can restore the fatty acid oxidation mechanism which constitutes the main energy source for the myocardium. Therefore, these results indicate that l-CARNITINE is a useful therapeutic agent for the treatment of congestive heart failure in combination with traditional pharmacological therapy.
The therapeutic potential of CARNITINE in cardiovascular disorders.
Clin Ther (UNITED STATES) Jan-Feb 1991, 13 (1) p2-21; discussion 1
The naturally occurring compound L-CARNITINE plays an essential role in fatty acid metabolism. It is only by combining with CARNITINE that the activated long-chain fatty acyl coenzyme A esters in the cytosol are able to be transported to the mitochondrial matrix where beta- oxidation occurs. CARNITINE also functions in the removal of compounds that are toxic to metabolic pathways. Clinical evidence indicates that CARNITINE may have a role in the management of a number of cardiovascular disorders. Supplemental administration of CARNITINE has been shown to reverse cardiomyopathy in patients with systemic CARNITINE deficiency. Experimental evidence obtained in laboratory animals and the initial clinical experience in man indicate that CARNITINE may also have potential in the management of both chronic and acute ischemic syndromes. Peripheral vascular disease, congestive heart failure, cardiac arrhythmias, and anthracycline-induced cardiotoxicity are other cardiovascular conditions that may benefit from CARNITINE administration, although at this time data on the use of CARNITINE for these indications are very preliminary. (53 Refs.)
Dilated cardiomyopathy due to primary CARNITINE deficiency
Squarcia Pediatr Med Chir (ITALY) Mar-Apr 1986, 8 (2) p157- 61
A case of a 3 and a half years old girl with severe congestive heart failure and typical picture of dilated cardiomyopathy is presented. The serum level of CARNITINE (17.2 micromoles/l, versus 44.1 +/- 12.2 micromoles/l, normal value for age) and the histologic and biochemical evaluation of quadriceps muscle tissue confirmed the diagnosis of primary deficit of CARNITINE. L-CARNITINE (2 gr. three times a day p.o.) was added to anti-congestive therapy. After 8 weeks of therapy, the general and cardiocirculatory conditions are much improved. The physiopathology of dilated cardiomyopathy due to deficit of CARNITINE are discussed. An early diagnosis and an early substitutive therapy with L-CARNITINE dramatically improve the outcome of the disease.
L-Carnitine and its role in medicine: A current consideration of its pharmacokinetics, its role in fatty acid metabolism and its use in ischaemic cardiac disease and primary and secondary L-carnitine deficiencies
Epitheorese Klinikes Farmakologias kai Farmakokinetikes (Greece), 1996, 14/1 (11-64)
L-Carnitine (L-beta-hydroxy-4-N-trimethylaminobutyric acid) is an essential nutrient in animals and humans, which is synthesised endogenously, mainly in liver and kidney, or obtained from diet, with principal sources red meat in adults and human milk in infants. L-Carnitine is a cofactor of several enzymes, including carnitine- acylcarnitine translocase embedded in the inner mitochondria membrane, and two acylcarnitine (palmitoyl) transferases I and II, located respectively in the outer and inner mitochondrial membrane; these biomolecules are required in mammalian tissues to transfer long-chain acyl CoAs across the inner membrane for beta-oxidation in the matrix. Furthermore, intramitochondrial L-carnitine and the matrix enzyme L-carnitine acetyltransferase can react with short- and medium-chain acyl CoAs to produce acylcarnitines, which can be shuttled out of mitochondria. Through this mechanism, L-carnitine is able to modulate the intracellular concentrations of free CoA and acetyl CoA via reversible formation of acetylcarnitine. Therefore, besides shuttling long-chain fatty acids into mitochondria, L-carnitine facilitates the oxidation of pyruvate and branched-chain ketoacids and, by preventing their accumulation, it contributes to the protection of cells from the potentially membrane-destabilising acyl CoAs. In the absence of L-carnitine, the accumulation of free fatty acids in the cytoplasm produces a toxic effect on the cell, and an energy deficit arises from the unavailability of fatty acids within the mitochondria. L- Carnitine is present in tissues and biological fluids in free and esterified forms. In humans, acylcarnitine esters account for about 25% of total L-carnitine in serum and for about 15% of total L-carnitine in liver and skeletal muscle. Total L-carnitine concentration in human tissues is higher in the heart and skeletal muscle (3.5-6.0 and 2.0-4.6 micromol/g, respectively) than in the liver and the brain (1.0-1.9 and 0.5-1.0 micromol/g, respectively): these values reflect the higher rates of fatty acid oxidative metabolism in the former tissues. The pharmacokinetics of exogenously administered L-carnitine have not been completely described. In the case of L- carnitine preparations from Sigma Tau Pharmaceuticals, peak plasma concentrations of free L- carnitine of 25 and 91 micromol/l have been attained 3 and 3,5 hours following single oral 30 and 100 mg/kg doses, respectively. L-Carnitine is actively transported into tissues via a saturable system, although passive diffusion also occurs. The apparent volume of distribution is about 37 l. The compound is likely metabolised in humans by partial conversion to acyl-carnitine esters and therefore is eliminated through the kidneys. The portion of a dose of L-carnitine excreted in the urine within 24 hours depends on the route of administration; thus, after an intravenous dose 86% has been recovered, in contrast to 7% of a dose recovered within 24 hours after an oral dose. Faecal elimination accounts for less than 2% of a dose. In healthy volunteers, the biological half-life of L- carnitine varies from 3 to 12 hours, depending on the dosage schedule. Over the past decade many clinical trials have suggested that L-carnitine may be administered to patients with ischaemic cardiac disease. The rationale for the use of L-carnitine in such patients initially originated from the findings that myocardial L-carnitine concentrations are lower in patients with fatal myocardial infarction, due to an increased lactate production and decreased energy output of cardiac muscle, than in those dying from non-cardiac causes. L-Carnitine has been shown to improve pyruvate metabolism, to reduce lactate production and acidosis and to act as a scavenger of toxic catabolic products of free fatty acids, which accumulate in the heart during ischaemia. Also, there is evidence for skeletal muscle L-carnitine deficiency in some patients with atherosclerotic vascular disease; therefore, L- carnitine supplementation may have potential to improve skeletal muscle metabolic and mechanical function. This double effect in cardiac and skeletal muscle makes L- carnitine attractive for patients with ischaemic heart disease; L-carnitine seems to play an important role, not only by enhancing carbohydrate utilisation, but also by reducing FFA toxicity and acting as a metabolic modulator in the heart.
Serum levels of carnitine in chronic fatigue syndrome: clinical correlates.
Neuropsychobiology (SWITZERLAND) 1995, 32 (3) p132-8
Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in chronic fatigue syndrome (CFS) patients. One previous investigation has reported decreased acylcarnitine levels in 38-CFS patients. We investigated 35 CFS patients (27 females and 8 males); our results indicate that CFS patients have statistically significantly lower serum total carnitine, free carnitine and acylcarnitine levels, not only lower acylcarnitine levels as previously reported. We also found a statistically significant correlation between serum levels of total and free carnitine and clinical symptomatology. Higher serum carnitine levels correlated with better functional capacity. These findings may be indicative of mitochondrial dysfunction, which may contribute to or cause symptoms of fatigue in CFS patients.
Acylcarnitine deficiency in chronic fatigue syndrome.
Clin Infect Dis (UNITED STATES) Jan 1994, 18 Suppl 1 pS62-7
One of the characteristic complaints of patients with chronic fatigue syndrome (CFS) is the skeletal muscle- related symptom. However, the abnormalities in the skeletal muscle that explain the symptom are not clear. Herein, we show that our patients with CFS had a deficiency of serum acylcarnitine. As carnitine has an important role in energy production and modulation of the intramitochondrial coenzyme A (CoA)/acyl-CoA ratio in the skeletal muscle, this deficiency might induce an energy deficit and/or abnormality of the intramitochondrial condition in the skeletal muscle, thus resulting in general fatigue, myalgia, muscle weakness, and postexertional malaise in patients with CFS. Furthermore, the concentration of serum acylcarnitine in patients with CFS tended to increase to the normal level with the recovery of general fatigue. Therefore, the measurement of acylcarnitine would be a useful tool for the diagnosis and assessment of the degree of clinical manifestation in patients with CFS.
Could L-carnitine be an acute energy inducer in catabolic conditions?
Dev Med Child Neurol (ENGLAND) Mar 1997, 39 (3) p174-7
Serum free carnitine levels in five children (aged between 2.5 months and 4 years) with the findings of septic shock without disseminated intravascular coagulopathy and seven children (aged between 1.5 and 6.5 years) with the first attack of idiopathic status epilepticus were compared with those of eight healthy children (aged between 2.5 months and 5 years). Serum free carnitine levels showed a statistically significant decrease in the sepsis (mean 51.5 +/- 19 mg/L) and status epilepticus groups (mean 4.1 +/- 12.4 mg/L) (P = 0.006 and P = 0.001, respectively) when compared with the controls (mean 90.8 +/- 17.2 mg/L).
Bacterial carnitine metabolism.
FEMS Microbiol Lett (NETHERLANDS) Feb 1 1997, 147 (1) p1-9
L-(-)-Carnitine is a ubiquitously occurring substance, essential for the transport of long-chain fatty acids through the inner mitochondrial membrane. Bacteria are able to metabolize this trimethylammonium compound in three different ways. Some, especially Pseudomonas species, assimilate L-(-)-carnitine as sole source of carbon and nitrogen. The first catabolic step is catalysed by the L-(-)-carnitine dehydrogenase. Others, for instance, Acinetobacter species, degrade only the carbon backbone, with formation of trimethylamine. Finally, various members of the Enterobacteriaceae are able to convert carnitine, via crotonobetaine, to gamma- butyrobetaine in the presence of C and N sources and under anaerobic conditions. This two-step pathway, including a L- (-)-carnitine dehydratase and the crotonobetaine reductase, was demonstrated in Escherichia coli. The DNA sequence encompassing the cai genes of E. coli, which encode the carnitine pathway, has been determined. Some bacteria are also able to metabolize the non-physiological D-(+)-carnitine, which results as a waste product in some chemical procedures for L-(-)-carnitine production based on the resolution of racemic carnitine.
Release of ischemia in paced rat Langendorff hearts by supply of L-carnitine: role of endogenous long-chain acylcarnitine.
Mol Cell Biochem (NETHERLANDS) Mar 9 1996, 156 (1) p87-91
Rat Langendorff hearts perfused with media that do not contain erythrocytes or fluorocarbon as oxygen carriers are borderline aerobic during 5 Hz pacing. This follows from the release of catabolic products measured: lactate, urate and Iysophosphatidyl-choline (IysoPC). Addition of L- carnitine to the perfusion medium reduced the level of these compounds, while the release of long-chain acylcarnitine (LCAC) increased. Previously, we found (Biochim Biophys Acta 847:62-66,1985) that micromolar LCAC protects membranes during reperfusion after ischemia. Therefore, the observed inverse relation between LCAC and the other compounds measured suggests that LCAC is the basis of an acute relief of imminent ischemia by carnitine addition. LCAC may be released from various cell types, including vascular endothelium, as demonstrated. The cationic amphiphilic nature of LCAC is responsible for protection of membrane functions in imminent ischemia.
Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock
British Journal of Cancer (United Kingdom), 1995, 72/5
Inappropriate hepatic lipogenesis, hypertriglyceridaemia, decreased fatty acid oxidation and muscle protein wasting are common in patients with sepsis, cancer or AIDS. Given carnitine's role in the oxidation of fatty acids (FAs), we anticipated that carnitine might promote FA oxidation, thus ameliorating metabolic disturbances in lipopolysaccharide (LPS)- and methylcholanthrene-induced sarcoma models of wasting in rats. In the LPS model, rats were injected with LPS (24 mg kg-1 i.p.), and treated with carnitine (100 mg kg-1 i.p.) at- 16, - 8, 0 and 8 h post LPS. Rat health was observed, and plasma inflammatory cytokines and triglycerides (TG) were measured before and 3 h post LPS. In the sarcoma model, rats were implanted subcutaneously with tumour, and treated continuously with carnitine (200 mg kg-1 day-1 i.p.) via implanted osmotic pumps. Tumour burden, TG and cytokines were measured weekly for 4 weeks. Carnitine treatment significantly lowered the tumour-induced rise in TG (% rise) in the sarcoma model (700 plus or minus 204 vs 251 plus or minus 51, P<0.03) in control and carnitine groups respectively. Levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-cc (TNF- alpha) (pg ml-1) were also lowered by carnitine in both LPS (IL-1beta: 536 plus or minus 65 vs 378 plus or minus 44: IL-6: 271 plus or minus 29 vs 222 plus or minus 32; TNF-alpha: 618 plus or minus 86 vs 367 plus or minus 54, P less than or equal to 0.02) and sarcoma models (IL-1beta: 423 plus or minus 33 vs 221 plus or minus 60; IL-6: 222 plus or minus 18 vs 139 plus or minus 38; TNF-alpha: 617 plus or minus 69 vs 280 plus or minus 77, P less than or equal to 0.05) for control and carnitine groups respectively. We conclude that carnitine has a therapeutic effect on morbidity and lipid metabolism in these disease models, and that these effects could be the result of down- regulation of cytokine production and/or increased clearance of cytokines.
L-carnitine deficiency in AIDS patients
AIDS (United Kingdom), 1992, 6/2 (203-205)
Objective: To evaluate carnitine (3-hydroxy-4-N-trimethyl- ammoniobutanoat e) deficiency in AIDS patients by measuring serum total, free and short-chain carnitine concentrations. Design: We conducted an open study. Setting: All patients were seen at the Infectious Diseases Clinic, Universita 'La Sapienza', Rome, Italy. Patients, participants: Twenty-nine AIDS patients, aged 27-41 years, with a previous history of drug use; and 14 healthy age- and sex-matched controls were studied. Interventions: Study subjects were administered 500-800 mg zidovudine daily for 2 to 28 months (8 plus or minus 6 months). Main outcome measures: Carnitine deficiency was suspected in study participants prior to data collection because of previously reported cardiac symptoms, muscle weakness, hypometabolism and/or cachexia. Results: A marked decrease in total and free carnitine was observed in 21 (72%) subjects Nine of these patients also had low levels of short-chain carnitine. Conclusions: AIDS patients may become carnitine-depleted and therefore at risk for alterations in fatty-acid oxidation and energy supply.
Carnitine and acetyl-L-carnitine content of human hippocampus and erythrocytes in Alzheimer's disease
Journal of Nutritional and Environmental Medicine (United Kingdom), 1995, 5/1 (35-39)
We have studied carnitine and acetyl-L-carnitine content of hippocampus and erythrocytes from Alzheimer's disease patients and elderly control subjects. Carnitine content was similar in erythrocytes from Alzheimer's disease patients and controls, but in contrast acetyl-L-carnitine content was significantly lower in the Alzheimer's disease patients compared with control subjects. On post-mortem samples from hippocampus, carnitine and acetyl-L-carnitine content did not differ significantly between patients when related to the protein content.
Rationales for micronutrient supplementation in diabetes.
Med Hypotheses (ENGLAND) Feb 1984, 13 (2) p139-51
Available evidence--some well-documented, some only preliminary--suggests that properly-designed nutritional insurance supplementation may have particular value in diabetes. Comprehensive micronutrient supplementation providing ample doses of antioxidants, yeast-chromium, magnesium, zinc, pyridoxine, gamma-linolenic acid, and carnitine, may aid glucose tolerance, stimulate immune defenses, and promote wound healing, while reducing the risk and severity of some of the secondary complications of diabetes. (125 Refs.)
Carnitine metabolism during fasting in dogs. Rodriguez J; Bruyns J; Askanazi J; DiMauro W; Bordley J 4th; Elwyn DH; Kinney JW. Surgery 1986 Jun; 99(6): 684-7 PMID: 3520914 UI: 86236032 During starvation, a series of changes in whole body fuel use occur that result in conservation of fuel, particularly protein. Use of fat stores for ketone production and direct oxidation of fat as a primary fuel are characteristic of starvation. However, the mechanism by which this change develops is unclear. Carnitine is an important compound in the control of fat metabolism, since long-chain free fatty acids must be coupled with it to cross the mitochondrial membrane. This study attempts to define, in the fasting dog model, the interaction between plasma and muscle carnitine, its acyl esters, and the energy substrates available. Eight adult beagle dogs were studied during an 8-day period of starvation. Muscle and plasma were analyzed for free carnitine (FC), acid-soluble fraction, and long-chain esters (LCE), as well as substrate hormone profiles. Total carnitine (TC) and short- chain esters (SCE) were calculated. Muscle was analyzed for carnitine palmityl transferase activity (CPT). These measurements were performed on days 3, 5, and 8. There was a significant (p less than 0.05) loss in weight on days 3, 5, and 8. TC and FC increased significantly (p less 0.05) only on day 8; this occurred simultaneously with a significant (p less than 0.05) decrease in CPT. It was preceded by a significant (p less than 0.05) and persistent increase in plasma TC, FC, and LCE that developed on day 3. During starvation there was an increase in plasma carnitine levels before changes in muscle. The increase in muscle carnitine occurred between days 5 and 8 of starvation and seemed to be associated with a fall in CPT. This may be responsible either for or secondary to the decrease in metabolic rate that occurs during prolonged starvation.
