Doses Of L-carnitine Research Articles

L-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.

Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored. Female C57 mice (48weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P<0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P<0.05). At the 5mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells. This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.

Ameliorative effects of L-carnitine as an antioxidant against testicular toxicity induced by AlCl3 in male albino rats.

The goal of this study was to investigate the potential protective effect of L-carnitine (20 mg/kg bw, 1/20 LD 50) against aluminum chloride (AlCl3) on the quality of the male rats' testicles and sperm, as well as to determine whether or not the effects of AlCl3 could be counteracted by using L-carnitine as an antioxidant. Six groups of 36 adult male albino rats (n=6) were randomly formed. In Group I (Gp I), saline injection was given orally as a control. Group II (Gp II) was injected orally with 75 mg/kg body weight of L-carnitine. Group III (Gp III) was given a high dose of L-carnitine (150 mg/kg body weight) orally, while Group IV (G IV) was given a low dose of AlCl3 (20 mg/kg body weight). Group V (Gp V) was given an oral injection of AlCl3 (20 mg/kg) and L-carnitine (75 mg/kg body weight). Group VI (Gp VI) was given AlCl3 at a dose of 20 mg/kg and L-carnitine at a dose of 150 mg/kg body weight for 60 days. The reproductive capacity of each group was assessed. Thus, in addition to histopathological analysis and the comet assay to evaluate sperm DNA deterioration, final body weight, testicular weight change, and sperm analysis were carried out. The findings revealed that AlCl3 caused a significant decrease in final body weight, relative weight of sex organs, sperm concentration, motility and viability, serum testosterone concentration, and a significant increase in sperm abnormalities. Furthermore, AlCl3 caused visible changes in the histological structure of the testis. L-carnitine treatment alleviated the harmful effects of AlCl3, as evidenced histopathologically by a noticeable improvement in testis tissues. When it comes to treating AlCl3-induced reproductive toxicity in male rat testes, L-carnitine shows promise.

Effects of Dietary Supplementation of L-Carnitine and Mannan-Oligosaccharides on Growth Performance, Selected Carcass Traits, Content of Basic and Mineral Components in Liver and Muscle Tissues, and Bone Quality in Turkeys.

The study aimed to determine the effect of L-carnitine and Bio-Mos administration on selected production performance, slaughter parameters, elemental and mineral content of liver, breast and thigh muscles, and physical, morphometric, strength and bone mineral composition parameters of turkeys. The experiment was conducted on 360 six-week-old Big-6 turkey females, randomly divided into three groups of 120 birds each (six replicates of 20 birds). The turkeys of the control group were fed standard feed without additives; group II was fed with drinking water, a preparation containing L-carnitine at a dose of 0.83 mL/L, while group III was provided mixed feed with 0.5% Bio-Mos. The addition of L-carnitine and Bio-Mos increased body weight at 16 weeks (p = 0.047) and reduced the proportion of fat in the breast muscle (p = 0.029) and liver (p = 0.027). It also modified the content of some minerals in breast muscle, thigh muscle, liver, and bone. Furthermore, the addition of L-carnitine and Bio-Mos increased bone mass and length and modified the value of selected morphometric and strength parameters. The results indicate a positive effect of the applied feed additives on selected rearing indices and carcass quality while improving the elasticity and fracture toughness of the femur. There is a need for further research to determine optimal doses of L-carnitine and Bio-Mos in poultry nutrition.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial β-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial β-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

The effect of L-carnitine administered to pregnant mice on reproductive performance of female offsprings

Carnitine was detected at the beginning of the previous. In the last 30 years, interest in the metabolism and functions of carnitine has steadily increased. Carnitine plays an essential role in fatty acid metabolism by facilitating the transport of long-chain free fatty acids into the mitochondrial matrix, making them available for β-oxidation, which is the most efficient metabolic pathway for energy production. The present study was performed to determine the effects of L-carnitine administered to pregnant mice on some parameters of reproductive performance for their female offspring. Sixty healthy female mice (age: 6 weeks) were used in this study, and divided into two equal groups including control group (mothers administered distilled water during gestation period)and treated group (mothers administered 1 mg/Kg L-carnitine during gestation period). Blood samples were taken from their female offspring for assessment of serum hormones (FSH, LH and E2). Also, weight of reproductive system for female offspring was recorded, and then histological sections were prepared for the uterus and ovary to measure the diameters uterine gland and ovary, in addition to measure endometrial thickness. Significant elevation (P&lt;0.01) was observed in the levels of serum gonadotropins (FSH and LH) and E2 for the treated group as compared to the control group. Weight of female reproductive system for the treated group was highly significant increased (P&lt;0.01) as compared to the control group. Also, significant increment (P&lt;0.05) was noticed in the thickness of endometrium for the treated as compared to the control group. Similarly, diameters of ovary and uterine glands for treated group were increased significantly (P&lt;0.05) when compared to the control group. Conclusion: Administration low doses of L-carnitine to pregnant mice have positive effects on reproductive performance of their female offspring. Further studies are recommended to investigate effects of L-carnitine to pregnant mice on oogenesis for their female offspring.

Histological study of L-carnitine effect against acute hepatotoxicity after cytarabine chemotherapy in male rats

Hepatotoxicity is a common clinical manifestation associated with a wide range of anticancer therapies. Because of the inherent toxicity of anticancer therapies, oncologists must maintain a broad understanding of their effects on the body, including the liver. Therefore, the study was conducted to examine the effects of two doses of L-carnitine on damaged liver as a result of giving cytarabine. Twenty-four male rats were used in the experiment. The rats divided to four group each group with six rats,the first group injected normal saline intraperitoneally and set as control group(G1), the second group injected cytarabine 25 mg/kg/bw, intraperitoneally and set as (G2), the third group injected cytarabine 25 mg/kg/bw and 50 mg/kg/bw, L-carnitine intraperitoneally and set as (G3), the fourth group injected cytarabine 25 mg/kg/bw and 300 mg/kg/bw, L-carnitine intraperitoneally and set as (G4), the study showed that use of L-carnitine reduced the harmful effect of cytarabine in the body when compared to other groups that were injected only with cytarabine at level of (p-value &lt;0.05).The rats treated with L-carnitine have shown significant elevation in CAT and SOD and reduction of the level of MDA.

Protective effect of l-carnitine on oxidative stress in the liver of acute hepatotoxicity male ratsafter cytarabine chemotherapy

Hepatotoxicity is a common clinical manifestation associated with a wide range of anticancer therapies. Because of the inherent toxicity of anticancer therapies, oncologists must maintain a broad understanding of their effects on the body, including the liver.Therefore, the study was conducted to examine the effects of two doses of L-carnitine on damaged liver as a result of giving cytarabine. Twenty-four male rat were used in the experiment. The rats divided to four group each group with six rats,the first group injected normal salineintraperitoneally and set as control group(G1),the second group injected cytarabine 25 mg/kg/bw intraperitoneally and set as (G2), the third injected cytarabine 25 mg/kg/bw and 50 mg /kg/bw L-carnitine intraperitoneally and set as (G3), the third injected cytarabine 25 mg/kg/bw and 300mg/kg/bw L-carnitine Intraperitoneally and set as(G4), the study showed that use of L-carnitine reduced the harmful effect of cytarabinein the body when compared to the group that was injected only with cytarabineat level of (p-value &lt;0.05). ALT show a significant increase in G2 when compared to other groups the mean value was (104±7.697, 134.66±13.08, 105.66±5.89, 94.33±3.5) for groups: control, cytarabine,50mg/kg/bw &amp; 300mg/kg/bw ofL-carnitine respectively;,,

The effects of l-carnitine supplementation on inflammatory factors, oxidative stress, and clinical outcomes in patients with sepsis admitted to the intensive care unit (ICU): study protocol for a double blind, randomized, placebo-controlled clinical trial

BackgroundSepsis is a common cause for admission to the intensive care unit (ICU), and its incidence has been increasing. It is associated with a significant increase in serum inflammatory biomarkers such as C-reactive protein (CRP) and cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF). Sepsis is also associated with pathophysiological changes that include fluid accumulation in the lungs, eventually leading to acute respiratory distress syndrome (ARDS), tissue edema, hypotension, and acute kidney injury (AKI). Conventional therapies include antibiotics, but these may have important adverse effects, so novel therapeutic approaches are required. In animal studies, l-carnitine improves antioxidant status, and in some clinical trials, it has been shown to reduce inflammation. It has also been shown to improve respiratory distress and help maintain coenzyme A homeostasis, metabolic flexibility, promoting the normal function of the tricarboxylic acid (TCA) cycle, and oxidation of fatty acids by peroxisomes. We aim to determine the effects of very high doses of l-carnitine on inflammatory factors, oxidative stress, and clinical outcomes of patients with sepsis in ICU.Method and designIn this double-blind, randomized controlled clinical trial, we will use block randomization of 60 patients with sepsis, aged between 20 and 65 years from Al-Zahra Hospital, Isfahan, Iran. The intervention group (n = 30) will receive three capsules of l-carnitine (each capsule contains 1000 mg l-carnitine; totally 3000 mg/day) for 7 days, and a control group (n = 30) will receive a placebo with the same dose and for the same duration in addition to usual care. At baseline, scores for clinical and nutritional status (Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), Quick SOFA (qSOFA), and NUTRIC Score) will be assessed. At beginning and end point of the study, inflammatory markers (CRP, erythrocyte sedimentation rate (ESR)), oxidative stress status (total oxidative stress (TOS), total antioxidant capacity (TAC)), and clinical variables will be evaluated also. The mortality rate will be assessed within 28 days of the beginning of the intervention.DiscussionBecause of the anti-inflammatory and antioxidant properties of l-carnitine, it is possible that using a high dose of 3000 mg daily of this nutritional supplement may reduce inflammation and oxidative stress and improve subsequent mortality of critically ill patients with sepsis.Trial registrationIranian Registry of Clinical Trials IRCT20201129049534N1. Registered on 2 May 2021.

Development and validation of an UHPLC-Orbitrap-HRMS method for rapid determination of endogenous L-carnitine in patients on hemodialysis/peritoneal dialysis and its application to promote rational drug use.

BackgroundL-carnitine is an endogenous vitamin-like amino acid derivate which plays an essential role in energy metabolism and can be easily lost via dialysis. Deficiency of L-carnitine has great effects on many aspects of bodily functions. To determine the deficiency degree and adjust the supplementation dose, a rapid, sensitive, and specific method for the detection of endogenous L-carnitine in the plasma of dialysis patients using ultra-high performance liquid chromatography-Orbitrap high resolution mass spectrometry (UHPLC-Orbitrap-HRMS) was developed and validated.MethodsThe plasma samples were processed by protein precipitation and centrifugation before analysis using UHPLC-Orbitrap-HRMS. Sample separation was achieved with a hydrophilic interaction liquid chromatography (HILIC) column, using an isocratic elution with a runtime of 5 min. The separated analytes were detected by positive ionization mode in full scan mode and targeted-single ion monitoring (t-SIM) mode. Mildronate was used as the internal standard (IS).ResultsAll the plasma could be detected in the range of 6.169 to 197.394 µM, with adequate accuracy, precision, and recovery. The method was validated in fortified validation with relative standard deviations (RSD) 5.15–8.74%. This method was applied to the analysis of 105 dialysis patients and 39 healthy participants, the results revealed that peritoneal dialysis patients without L-carnitine supplementation should pay more attention to L-carnitine monitoring, meanwhile, all the hemodialysis patients were advised to be routinely given a full dose of L-carnitine, no matter whether they had taken L-carnitine or not.ConclusionsThis study developed a simple and rapid UHPLC-Orbitrap-HRMS method for detection of endogenous L-carnitine in dialysis patients, which could be useful to promote rational drug use.

Genetic predisposition in pediatric acute myocarditis: a pilot study

Abstract Background Myocarditis is an inflammatory disease of the heart muscle with a wide range of clinical presentations, from asymptomatic to cardiogenic shock and death. Although acute myocarditis is rare in pediatric population, it is caused by common viral infections, like parvovirus B19 or enteroviruses. Limited scientific evidence supports the existence of a genetic background that could underlay the susceptibility to virus-induced myocarditis. Purpose The aim of the present study was to identify mutations in genes associated with cardiomyopathies, that could possibly underly acute myocarditis in pediatric patients with biopsy-proven parvovirus B19 infection, verified by real time PCR. Methods Nine pediatric patients presented in our center with acute myocarditis were genotyped with next generation sequencing using Clinical Exome Solution kit (Sophia Genetics) covering 4493 disease-related genes. Variant pathogenicity was accessed according to guidelines by American College of Medical Genetics (2015). Results Genetic analysis revealed that three of the nine patients were found positive for pathogenic/likely pathogenic mutations in TTR, ABCC6 and SLC22A5 genes. The patient that carried the SLC22A5 variant initially received telbivudine and her ejection fraction was improved from 20% to 45%. Genetic test results suggested that the patient may suffer from mild L-carnitine deficiency. Oral supplementation with high dose of L-carnitine during one month period improved dramatically her EF to normal (65%). The patient that carried the ABCC6 mutation, also carried a variant of unknown significance in MYH7 gene. Four patients carried variants of unknown significance. The variants of unknown significance detected in MYBPC3, SCN5A, and MYH7 genes are of particular interest since they accumulate evidence of pathogenicity. Two patients did not harbor any mutations. Conclusion A significant proportion of rare variants in genes associated with cardiomyopathies has been identified in a small cohort of pediatric patients with parvovirus-induced acute myocarditis. The findings of our study, although limited, support the existence of a genetic background that could function as a predisposing factor influencing the clinical course of the disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Onassis Foundation

Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock.

Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90‐day mortality benefit from L‐carnitine. The independent predictive value of each pretreatment metabolite concentration, adjusted for L‐carnitine dose, on 90‐day mortality was determined by logistic regression. A grid‐search analysis maximizing the Z‐statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L‐carnitine responsive patients. Threshold concentrations were further assessed by hazard ratio and Kaplan‐Meier estimate. Accounting for L‐carnitine treatment and dose, 11 1H‐NMR metabolites and 12 acylcarnitines were independent predictors of 90‐day mortality. Based on the grid‐search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L‐carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L‐carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90‐day sepsis mortality. Our proof‐of‐concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.

Effect of different doses of L-carnitine on fertility of the male reproductive system of albino rats

In the current study, different doses of L-carnitine were tested on 20 healthy albino male rats to determine the effect of L-carnitine on the physiological and histological parameters of the reproductive system. The animals were distributed into four groups, the first group was the control group. In this group the animals were not given any dose of L-carnitine, The second group was the treatment group and in this group the animals were dosed with L-carnitine at a dose of 28 mg / kg, and the third group was the double dose group, as the animals dosed 56 mg / kg of carnitine, while the fourth group was dosed with an overdose when they were dosed with 112 mg / kg of L- carnitine . The results of the hormonal study showed that the double dose and the double dose group led to a significant decrease in the level of ICSH, SSH and testosterone, while the treatment group had no significant differences compared to the control group. The treatment group did not notice significant differences in the level of male hormones compared with the control group. The results of the study showed that the sperm parameters of the treated group were normal, while the sperms in the double and excessive group of L-carnitine showed the presence of twisted tailed sperm and the occurrence of deformation in the sperm head. The testicular tissue sections in the L-carnitine treatment group showed normal spermatogenesis during spermatogenesis, spermatogenesis and Leydig cells, while the L-carnitine double group showed a low number of mature sperms. Also, in the testicular sections of the doubled L-carnitine group, the occurrence of histological necrosis of the testicles was found. Additionally, the stages of spermatogenesis are not clear.

Neuroprotective Effect of L-carnitine. Focus on Changing Mitochondrial Function

Introduction: In this study, the neuroprotective effect of L-carnitine administered per os in a dose of 25 mg/kg – 800 mg/kg was evaluated. The effects of L-carnitine on changes in mitochondrial function were also studied.&#x0D; Materials and Methods: The neuroprotective effect and mitochondrial function were evaluated in a model of perma­nent focal ischemia in Wistar-line rats. L-carnitine was administered to rats orally for 72 hours from the moment of modeling ischemia. On the 4th day after the ischemia simulation, the change in the respiratory function of the mito­chondria, the opening time of the mitochondrial permeability transition pore, the mitochondrial membrane potential, the concentration of intracellular calcium and the size of the cerebral necrosis zone were determined in rats’ brain supernatant.&#x0D; Results: As a result, it was found that the administration of L-carnitine contributed to the restoration of mitochondrial function and a decrease in the size of the brain necrosis zone. At the same time, the administration of L-carnitine in low doses (25 mg/kg – 100 mg/kg) did not have a significant effect on the change in the concentration of intracellular calcium. It should be noted that an increase in the dose of L-carnitine from 200 mg/kg to 800 mg/kg was not accom­panied by a significant increase in the therapeutic effect.&#x0D; Discussion: L-carnitine is one of the key biomolecules that directly affect metabolic processes. It is known that L-car­nitine acts as a ”shuttle” for long-chain fatty acids and thus can affect the alteration of mitochondrial function. Howev­er, the detailed nature of the mitochondriotropic action of L-carnitine has not been yet established. This was the focus of this study, which showed that the mitochondrion-oriented effect of L-carnitine is dose-dependent and expressed in the form of restoring the respiratory function of mitochondria, restoring the mitochondrial potential and increasing the latent opening time of the mitochondrial permeability transition pore, reducing the level of intracellular calcium.&#x0D; Conclusion: The study allowed us to expand our understanding of the L-carnitine neuroprotective effect and the effect of this compound on changes in mitochondrial function.&#x0D; Graphical abstract:

Liver-Oriented Acute Metabolic Effects of A Low Dose of L-Carnitine under Fat-Mobilizing Conditions: Pilot Human Clinical Trial.

The acute metabolic effect of low dosages of L-carnitine under fat-mobilizing conditions was investigated. Healthy subjects (Study 1: n=5; Study 2: n=6) were asked to fast overnight. Then, 30 min of aerobic exercise on a cycle ergometer was performed after supplementation, followed by a 3.5-h sedentary recovery phase. The following ingestion patterns were used: Study 1 (i) noningestion, (ii) 750 mg of L-carnitine (LC), and (iii) 750 mg of LC+50 g of carbohydrate (CHO); Study 2 (iv) noningestion, (v) 500 mg of LC, (vi) 30 mg of CoQ10, and (vii) 500 mg of LC+30 mg of CoQ10. The energy expenditure (EE) and nonprotein respiratory quotient (npRQ) were measured during the pre-exercise, postexercise, and recovery periods. Serum free carnitine, acetylcarnitine, total carnitine (Study 1 and 2), and ketone bodies (Study 2) were measured. The 750 mg LC treatment significantly facilitated fat oxidation during the recovery phases (p<0.05) without elevating EE. The higher fat oxidation associated with LC was completely suppressed by CHO. CoQ10 affected neither npRQ nor EE. npRQ was significantly correlated with the serum total ketone bodies (R=-0.68, p<0.001) and acetylcarnitine (R=-0.61--0.70, p<0.001). The highest correlation was found between acetylcarnitine and total ketone bodies immediately after exercise (R=0.85, p<0.001). In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.

L-Carnitine different doses affect serum and pancreas tissue Antioxidative defense and histopathology in STZ-induced diabetic rats

Diabetes mellitus is a global health issue that affects life expectancy and quality. In diabetic patients, the oxidation status is increased which has detrimental effects against homeostasis. L-carnitine showed anti-oxidative effects in different tissues, and also it was reported that L-carnitine levels reduced in patients with diabetes. In this study, we examined the administration of different doses of L-carnitine on antioxidants status in diabetic rats’ serum and pancreas. Forty-eight male rats (200 ± 10 g weight) were randomly selected and divided into 6 groups (n = 8) as follow; Group I, untreated control, group II, Diabetic control, group III-VI, diabetic rats which received 50, 100, 200 and 300 mg/kg/day L-carnitine by intraperitoneal injection for 35 days, respectively. At the end of the study, blood samples and pancreas tissue were collected and histopathology and anti-oxidant status were measured. Our results showed that antioxidative capacity was reduced in the diabetic rats. Between different L-carnitine doses, 300 mg/kg/day of L-carnitine showed significant effects than other doses. The highest dose of L-carnitine (300 mg/kg/day) in this study, significantly increased TAS (Total Antioxidant Status), SOD (Superoxide Dismutase) and GPX (Glutathione Peroxidase) levels in the pancreas and serum. Also, it improved pancreas histopathology compared to the diabetic control group. We conclude that L-carnitine administration has protective effects on the pancreas and serum of STZ-induced diabetic rats, and exerts these beneficial effects through hypoglycemic and antioxidant actions.

Efficacy of l-carnitine supplementation for management of blood lipids: A systematic review and dose-response meta-analysis of randomized controlled trials

Background and aiml-carnitine has an important role in fatty acid metabolism and could therefore act as an adjuvant agent in the improvement of dyslipidemia. The purpose of present systematic review and meta-analysis was to critically assess the efficacy of l-carnitine supplementation on lipid profiles. Methods and resultsWe performed a systematic search of all available randomized controlled trials (RCTs) in the following databases: Scopus, PubMed, ISI Web of Science, The Cochrane Library. Mean difference (MD) of any effect was calculated using a random-effects model.In total, there were 55 eligible RCTs included with 58 arms, and meta-analysis revealed that l-carnitine supplementation significantly reduced total cholesterol (TC) (56 arms-MD: −8.53 mg/dl, 95% CI: −13.46, −3.6, I2: 93%), low-density lipoprotein-cholesterol (LDL-C) (47 arms-MD: −5.48 mg/dl, 95% CI: −8.49, −2.47, I2: 94.5) and triglyceride (TG) (56 arms-MD: −9.44 mg/dl, 95% CI: −16.02, −2.87, I2: 91.8). It also increased high density lipoprotein-cholesterol (HDL-C) (51 arms-MD:1.64 mg/dl, 95% CI:0.54, 2.75, I2: 92.2). l-carnitine supplementation reduced TC in non-linear fashion based on dosage (r = 21.11). Meta-regression analysis indicated a linear relationship between dose of l-carnitine and absolute change in TC (p = 0.029) and LDL-C (p = 0.013). Subgroup analyses showed that l-carnitine supplementation did not change TC, LDL-C and TG in patients under hemodialysis treatment. Intravenous l-carnitine and lower doses (>2 g/day) had no effect on TC, LDL-C and triglycerides. Conclusionl-carnitine supplementation at doses above 2 g/d has favorable effects on patients' lipid profiles, but is modulated on participant health and route of administration.

Can L-carnitine prevent Cadmium-Induced Damage of the Developing Hippocampus?

Background: Cadmium is used in everyday life aspects. Hippocampus plays important role in the memory process and could be affected by cadmium exposure. L-carnitine is antioxidant, its role in neuroprotection is still not known. Aim of work: To assess effects of pre- and postnatal cadmium exposures on structure of principle cells (pyramidal and granular) of hippocampus in albino rats, and the potential role of L-carnitine. Material and methods: Pregnant female albino rats were used and divided into two major groups: I- Pregnancy and II- Lactation, each was further equally subdivided into 4 subgroups: Group Ia- Control. Group Ib- received cadmium from pregnancy day (PD)10 until delivery. Group Ic- received L-carnitine from PD7 until delivery. Group Id- received both L-carnitine from PD7 + cadmium from PD10 until delivery. Group IIa- Control. Group IIb- received cadmium from day 0-21. Group IIc- received L-carnitine from day 0-21. Group IId- received both L-carnitine+cadmium from day 0-21. Cadmium chloride was given orally by gastric lavage 4 mg/kg bodyweight/day. L-carnitine dose was given as 200 mg/kg/day orally by gastric lavage. The hippocampal specimens were collected from twelve male offspring of both age subgroups (newborn and 21 day old; 96 rats total) and were processed for light, electron microscopy and morphometry. Results: In cadmium received rats principle cells showed degenerative changes as pyknosis, cytoplasmic vacuoles, damaged mitochondria, indentation of nuclear membrane, and the morphometric data showed highly significant reduction in principle cells number and decreased principle cell layer thickness as compared to control. In cadmium+L-carnitine received rats the principle cells showed a very few swollen cells with little vacuoles, mildly dilated rough endoplasmic reticulum, and the morphometric results were improved approaching those of the control. Conclusion: cadmium damaged principle cells of dentate gyrus, CA3 and CA1 fields of the rat hippocampus. L-carnitine reduced the cadmium-induced neuronal damage.

Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues

This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received l-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of l-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.

Cardiometabolic responses to L-carnitine in obese women with knee osteoarthritis: a randomized, double-blind, placebo-controlled pilot study

This study aimed to investigate cardiometabolic responses to L-carnitine in obese women with knee osteoarthritis (OA). In this randomized double-blind, placebo-controlled trial, 50 obese women with mild to moderate knee OA were randomly allocated into 2 groups to receive 750 mg/d L-carnitine or placebo for 8 weeks. Anthropometric indices, blood pressure and atherogenic indices were measured before and after the intervention. Only 48 patients (23 in the L-carnitine group and 25 in the placebo group) completed the study. L-carnitine resulted in significant reduction in hip circumference (115.15±6.19 vs 113.57±4.89) compared with baseline (P=0.013); whilst it didn’t change body mass index, waist circumference, waist to hip and waist to height ratios significantly (P>0.05). L-carnitine led to significant reduction in systolic blood pressure compared with placebo group, adjusted for baseline values (P=0.020). Atherogenic indices didn’t change significantly in both groups through the study (P>0.05). No significant differences were observed in anthropometric measures and atherogenic indices between two groups after adjusting for baseline values and covariates (P>0.05). In conclusion, L-carnitine did not lead to significant changes in obesity-associated parameters and atherogenic indices in women with knee OA. However, long-term studies with higher doses of L-carnitine are needed to explore its efficacy as an anti-obesity and anti-atherogenic agent in OA patients.

L-carnitine for pegylated-l-asparaginase induced hepatotoxicity.

e21626 Background: Pegylated-L-asparaginase (PEG-Asp) treatment causes severe hepatoxicity in about 25% of adults. Two case reports suggest that L-carnitine may rapidly reverse PEG-Asp-induced hepatotoxicity. Methods: We retrospectively analyzed data from 11 consecutive patients from 3 centers receiving L-carnitine for PEG-Asp-related hepatotoxicity from 4/2014 to 4/2016. Eligible adults received L-carnitine for hepatotoxicity probably or definitely related to PEG-Asp. Total bilirubin (Tbili), ALT, or AST stabilization was defined as a variation within 10% from baseline maintained for 3 days. Improvement was defined as a decrease of ≥10% the prior day maintained for 3 days. Liver imaging included CT scans or ultrasounds. Results: The majority of patients were male, 91% (Table 1). Imaging on 7 patients showed hepatic steatosis in 2 (29%) prior to PEG-Asp and 5 (71%) after PEG-Asp. Median peak Tbili, ALT, and AST were 15.4 mg/dL (2.3-27.58), 194 IU/L (120-1491), and 119 IU/L (52-1064), respectively. Median days from hyperbilirubinemia to L-carnitine initiation was 4 (1-13). Median L-carnitine dose was 2,000 mg/day (1,880-4,450). Median days until Tbili, AST, and ALT improvement were 6.5 (4-14), 4 (2-19), and 3.5 (1-8), respectively. Median days until Tbili normalization was 34 (4-52). Improvement in Tbili, ALT, and AST within 8 days of L-carnitine was seen in 5, 19, and 11 patients, respectively. No adverse events were attributable to L-carnitine. Conclusions: L-carnitine for PEG-Asp-induced hepatotoxicity was safe and associated with stabilization and improvement in transaminitis and, to a lesser extent, hyperbilirubinemia. See table. [Table: see text]