Long-term L-carnitine Administration Research Articles

Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis.

Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. l-carnitine (2g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.

The role of L-carnitine in acetyl salicylic acid-induced acute gastric mucosal injury in rats

<b>Introduction</b>: The aim of this study was to determine the protective effects of L-carnitine on acetyl salicylic acid (ASA)-induced acute gastric mucosal injury through oxidant/antioxidant parameters and histopathological alterations in rat gastric tissues.<br /> <b>Material and methods: </b> Forty-two rats were randomly assigned to six groups: The control group received 1 mg/kg distilled water, while the other groups were pretreated with L-carnitine 50 mg/kg/day (LC), pantoprazole 40 mg/kg/day (PPI), ASA + LC (50 mg/kg/day), and ASA + PPI (40 mg/kg/day), for 21 days, respectively. On day 23, gastric mucosal injury was induced by a single intragastric administration of 600 mg/kg aspirin in ASA, ASA + LC, and ASA + PPI groups. The animals were killed 60 min after the administration of aspirin. The stomach of each animal was removed. Gastric mucosal injury was scored histopathologically (ulcer score). Tissue catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) and nitric oxide (NO) levels were also measured.<br /> <b>Results</b>: The ulcer score increased significantly in the ASA group, but this increase was not significantly inhibited by the administration of L-carnitine (2.71 ±1.0 vs. 2.57 ±0.5, p = 0.965). The CAT and GSH-Px activities were significantly reduced, whereas MDA and NO levels were significantly increased in the ASA group. Pretreatment with L-carnitine did not alter CAT or GSH-Px activities, but reduced MDA and NO levels insignificantly (p = 0.204 and p = 0.277, respectively).<br /> <b>Conclusions</b>: Long-term administration of L-carnitine did not improve the oxidative and histological parameters of acute gastric mucosal injury induced by ASA.

The effect of long-term oral L-carnitine administration on insulin sensitivity, glucose disposal, plasma concentrations of leptin and acylcarnitines, and urinary acylcarnitine excretion in warmblood horses

Background: Insulin resistance in horses is an emerging field of interest as it is thought to be a contributing factor in the pathogenesis of many equine conditions.Objectives: The objectives of the present study were to determine the effects of long-term oral administration of L-carnitine on insulin sensitivity, glucose disposal, plasma leptin concentrations and acylcarnitine spectrum both in plasma and urine.Animals and methods: Six 3-year-old healthy warmblood geldings were used. In a double blind 2 × 2 Latin square design at a dosage of 100 mg/kg body weight (BW)/day for 28 days the effects of oral supplementation of L-carnitine (as fumarate) were assessed. Glucose disposal and insulin sensitivity were measured by means of the euglycemic-hyperinsulinemic clamp technique. Radioimmunoassays were used to determine plasma leptin and insulin concentrations. Electrospray tandem mass spectrometry was used to assess acylcarnitines both in plasma and urine. Statistical analysis was performed using a linear mixed-effects model and P values <0.05 were considered significant.Results: Long-term L-carnitine administration did not affect insulin sensitivity. Plasma leptin and free carnitine concentrations in plasma and urine increased significantly (P = 0.047 and 0.000, respectively) following L-carnitine administration as well as short-chain acylcarnitines in plasma and urinary excretion of short- and medium-chain acylcarnitines.Conclusion and clinical relevance: Given the effects of oral administration of L-carnitine further clinical study is necessary in order to assess the potential beneficial effects in equine patients suffering from metabolic myopathies such as acquired multiple acyl-CoA dehydrogenase deficiency.Impact for human medicine: The current study supports the treatment rationale of short-chain acyl-CoA dehydrogenase deficiency in humans with L-carnitine at an oral dosage of 100 mg/kg BW/day.

Long-term L-Carnitine Administration reduces Erythropoietin Resistance in Chronic Hemodialysis Patients with Thalassemia Minor

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Long-term L-Carnitine Administration reduces Erythropoietin Resistance in Chronic Hemodialysis Patients with Thalassemia Minor

Background and Aim: Both thalassemia and carnitine deficiency represent independent causes of erythropoietin resistance, and thus anemia, in uremic patients. We evaluated the unknown long-term effects of L-carnitine administration in β-thalassemic on chronic hemodialysis. Methods: We studied twelve subjects (M = 8; F = 4) affected by β-thalassemia minor (β-thal; HbA2 level = 6.6 ± 0.6%) and forty non-thalassemic subjects (M = 24; F = 16) as controls (C), on chronic hemodialysis treatment. Patients and controls were at target hemoglobin levels (11–12g/dl) prior to the study and underwent to i.v. L-carnitine administration for a one year period-time. Results: Groups were comparable for age, gender, serum levels of hemoglobin (Hb), iron, ferritine, PTH and aluminum, transferrin saturation, and dialysis modalities. During the study both groups showed significant Hb increase and erythropoietin (EPO) decrease; as a difference, such changes emerged at the 3rd month in C but at the 8th month in β-thal. At start, during the dialysis session the erythrocyte MCV reduced in C but not in β-thal (65.3 ± 3.2 to 65.5 ± 3.2 fl; NS); along carnitine administration period, however, MCV during dialysis decreased also in β-thal, starting since the 9th month of treatment. Conclusion: This study provides evidence of the lowering of EPO resistance in β-thalassemia patients on hemodialysis due to long-term carnitine administration. Thus, prolonged carnitine supplementation should be suggested to patients on dialysis affected by β-thalassemia with poorly responsive anemia, or requiring large doses of erythropoietin.

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

Hepatocellular carcinoma is usually preceded by chronic inflammation. However, the molecular mechanism in hepatocarcinogenesis is not well known. Recently, we reported that mitochondrial dysfunction plays an important role in hepatocarcinogenesis via the production of free radicals. Furthermore, we proved that L-carnitine effectively protects mitochondrial function in vivo. Therefore, we investigated whether long-term administration of L-carnitine could prevent hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats that are often analyzed as a model of hepatocarcinogenesis. The results indicated that oxidative stress elicited from abnormally accumulated copper increased the amount of free fatty acids, thereby inducing mitochondrial dysfunction, resulting in cell death and enhanced secondary generation of reactive oxygen species, which were significantly inhibited by carnitine treatment. Finally, the occurrence of placental glutathione S-transferase-positive foci as a marker for preneoplastic lesions and hepatocarcinogenesis were significantly inhibited by L-carnitine. These facts suggest that mitochondrial injury plays an essential role in the development of hepatocarcinogenesis and that the clinical use of carnitine has excellent therapeutic potential in individuals with chronic hepatitis.

L-carnitine transport in kidney of normotensive, Wistar-Kyoto rats: effect of chronic L-carnitine administration.

To examine the effect of long-term administration of L-carnitine on L-carnitine transport in renal brush-border membrane vesicles (BBMVs) from normotensive, Wistar-Kyoto rats. Rats (n = 20) were orally administered 0.2 g carnitine/kg body weight per day for a total period of 8 weeks. Kinetic parameters of L-carnitine uptake were calculated by non-linear regression, and the relative abundance of the carnitine transporter, OCTN2, was determined by Western blot analysis. Initial rates and maximal overshoot levels of Na+-dependent L-carnitine transport were significantly reduced in BBMVs from L-carnitine-treated rats compared with untreated animals. Similarly, the maximal transport rate (Vmax) of OCTN2 was lower in treated rats. However, no differences were observed in the Michaelis constant (Km) or the diffusion constant (Kd) between the two groups of animals. The amount of OCTN2 protein was also decreased in L-carnitine-fed rats, this reduction being similar to that of the Vmax. These results were accompanied by an increase in the serum levels and also in the renal excretion of both free and esterified carnitine in treated rats, indicating that the long-term administration of L-carnitine leads to increased renal carnitine clearance. These findings suggest a downregulation of OCTN2 at the renal level, in the presence of high levels of carnitine.

Long-term administration of l-carnitine to humans: effect on skeletal muscle carnitine content and physical performance

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

Myocardial infarction and left ventricular remodeling: Results of the CEDIM trial

Left ventricular dilatation after acute myocardial infarction (MI) is a powerful predictor of progressive functional deterioration, culminating in heart failure and death. The most important determinants of post-MI left ventricular remodeling are the size of the infarct, the degree of residual stenosis in the infarct-related artery, and the viability of the infarct zone. In addition to reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may represent a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function. Ongoing studies with early metabolic intervention with carnitine in the acute phase of infarction may prove successful in protecting the microcirculation against ischemic damage and enhancing its ability to respond to blood flow resumption. The results of the multicenter, randomized, double-blind Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial suggest that the early and long-term administration of L-carnitine attenuates progressive left ventricular dilatation after acute anterior MI. Results show significant, consistent reductions in end-diastolic volume and end-systolic volume in patients who received L-carnitine compared with placebo. The ongoing CEDIM-2 trial (projected 4000 patients with acute MI) will assess the efficacy of L-carnitine in reducing the combined incidence of death and heart failure at 6 months. In addition to standard reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may be a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function by limiting infarct size, decreasing residual stenosis in the infarct-related artery, and increasing viability of the infarct zone. (Am Heart J 2000;139:S124-S130.)

Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration

We examined the efficacy of long-term L-carnitine administration for the treatment of heart failure caused by dilated cardiomyopathy in adult patients. To accomplish this, we studied 80 patients with moderate to severe heart failure (New York Heart Association classification III to IV) caused by dilated cardiomyopathy. This article reports on the nearly 3 years of follow-up data on patient mortality. Primary results will be published in the future. After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either L-carnitine (2 g/d orally) or placebo. There were no statistical differences between the 2 groups at baseline examination in clinical and hemodynamic parameters, such as ejection fraction, Weber classification, maximal time of cardiopulmonary exercise test, peak VO 2 consumption, arterial and pulmonary blood pressure, and cardiac output. After a mean of 33.7 ± 11.8 months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in the placebo group and 37 in the L–carnitine group. At the time of analysis, 63 patients were alive. There were 6 deaths in the placebo group and 1 death in the L-carnitine group. Survival analysis with the Kaplan-Meier method showed that patients’ survival was statistically significant ( P < .04) in favor of the L-carnitine group. L-carnitine appears to possess considerable potential for the long-term treatment of patients with heart failure attributable to dilated cardiomyopathy. (Am Heart J 2000;139:S120-S123.)

Cardiomegaly in the juvenile visceral steatosis (JVS) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after l-carnitine injection

The long-term administration of l-carnitine was very effective in preventing cardiomegaly in juvenile visceral steatosis (JVS) mice, which was confirmed by heart weight as well as the lipid contents in heart tissue. After i.p. injection of l-carnitine, the concentration of free carnitine in heart remained constant, although serum free carnitine level increased up to 80-fold. On the other hand, a significant increase in short-chain acyl-carnitine level in heart was observed. These results suggest that increased levels of short-chain acyl-carnitine, not free carnitine, might be a key compound in the protective effect of l-carnitine administration in JVS mice.

Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study

AbstractThe Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study

The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

慢性左室疾患患者の心機能および運動能力に及ぼすＬ‐カルニチンの慢性効果

To assess the clinical efficacy of L-camititine in chronic heart failure, we measured echocardiographic left ventricular dimensions, peak oxygen consumption (peak Vo2), and anaerobic threshold (AT) before and after a long-term administration of L-carnitine (1, 800 mg/day, 12 weeks) in 18 patients with left ventricular dysfunction (I to III in New York Heart Association fuhctional classification). Peak Vo2 and AT were determined by the continuous respiratory gas analysis during a symptom-limited maximal bicycle exercise test. The patiehts were divided into 2 groups according to the presence of exercise-induced ST depression (>0.1 mV) in the control exercise test: 9 patients with ST depression (Group I) and 9 patients without ST depression (Group II). In Group I, exercise-induced ST depression was significantly improved by the chrohic admihistratioh of L-carnitine (0.17±0.03 mV to 0.12±0.03 mV, mean±SE, P<0.05). Coincidentally both peak Vo2 and AT significantly increased after L-carnitine administration when compared to those before administration in Group I (21.3±2.5, 17.2±27 to 24.3±2.3, 20.2±2.3 ml/min·kg, re spectively, mean±SE, P<0.05). In Group II there was no sighificant change in electro cardiographic findings, peak Vo2, or AT by the drug administration. The intemal dimensions and the fractional shortening of the left ventricle were not altered by the L-carnitineadministration in both grotips. Thus, we conclude that L-carhitine can increase exercise capacity in patients with chronic heart failure when they are attended with exercise-induced ST depression, possibly by improving abnormalities in the myocardial fatty acidenergy metabolism during exercise.