Does L-carnitine prevent cadmium-induced damage in gastrointestinal contractility and histological changes in prepubertal rat / ¿La L-carnitina previene el daño inducido por cadmio en la contractilidad gastrointestinal y los cambios histológicos en ratas prepúberes?

SUMMARY: Cadmium (Cd) is the industrial and environmental toxic heavy metal which is found in air, water and soil. Cd, adversely affects many organs in humans such as kidney, intestine, liver, testis and lungs. L-carnitine (LC) is an important agent that plays essential role in energy metabolism. In our study, we aimed to work out whether LC application has any protective effect on intestinal contractility and morphologic damage of prepubertal rat duodenum on Cd-induced toxicity. Twenty eight prepubertal female Wistar rats were divided into four groups. The first group is control (C), second group; Cd group; Cadmium chloride was given 2 mg/kg 28 days with a one-day break by i.p. The third group; Cd+LC, which cadmium chloride was given 2 mg/kg i.p. and LC was given orally by gastric lavage. The LC dose was given as 75 mg/kg. The fourth group; LC, which only LC was given orally. The intestinal segments were isolated and suspended in tissue bath. Contractile responses were induced by acetylcholine (ACh) and relaxation was achieved with phenylephrine. Also the segments were examined for histological changes by light microscopy. Ach-induced contractions were higher in Cd+LC, LC, and control group compared to the Cd group in duodenal segments. The phenylephrine-induced relaxations were lower in Cd groups as compared with Control, Cd+LC and LC group in duodenal segments. In Cd group intestinal morphology was observed to be severely damaged whereas in Cd+LC group the damage was noticeably lower. Cd administration caused severe cellular damage and decreased gastrointestinal motility. Treatment with the LC has affected the gastrointestinal contractility and reduced the damage in intestinal morphology, which occured after Cd application.

El cadmio (Cd) es el metal pesado tóxico industrial y ambiental que se encuentra en el aire, el agua y el suelo. El Cd afecta negativamente a muchos órganos humanos, como los riñones, los intestinos, el hígado, los testículos y los pulmones. La L-carnitina (LC) es un agente importante que juega un rol esencial en el metabolismo energético. El objetivo de este estudio fue determinar si la aplicación de LC tiene algún efecto protector sobre la contractilidad intestinal y el daño morfológico del duodeno de rata prepuberal sobre la toxicidad inducida por Cd. Veintiocho ratas Wistar hembras prepúberes se dividieron en cuatro grupos. El primer grupo control (C), segundo grupo; grupo cd; Se administró cloruro de cadmio 2 mg/kg durante 28 días con un descanso de un día por vía i.p. El tercer grupo; Cd+LC, al que se administró cloruro de cadmio 2 mg/kg i.p. y LC se administró por vía oral mediante lavado gástrico. La dosis de LC se administró como 75 mg/kg. El cuarto grupo; LC, al cual solo LC se administraba por vía oral. Los segmentos intestinales fueron aislados y suspendieron en baño de tejido. Las respuestas contráctiles fueron inducidas por acetilcolina (ACh) y la relajación se logró con fenilefrina. También se examinaron los segmentos en busca de cambios histológicos mediante microscopía óptica. Las contracciones inducidas por Ach fueron mayores en Cd+LC, LC y el grupo control en comparación con el grupo Cd en los segmentos duodenales. Las relajaciones inducidas por fenilefrina fueron menores en los grupos Cd en comparación con el grupo Control, Cd+LC y LC en los segmentos duodenales. En el grupo Cd se observó que la morfología intestinal estaba severamente dañada mientras que en el grupo Cd+LC el daño fue notablemente menor. La administración de Cd causó daño celular severo y disminución de la motilidad gastrointestinal. El tratamiento con LC afectó la contractilidad gastrointestinal y redujo el daño en la morfología intestinal, que ocurría después de la aplicación de Cd.

Association between Levocarnitine Treatment and the Change in Knee Extensor Strength in Patients Undergoing Hemodialysis: A Post-Hoc Analysis of the Osaka Dialysis Complication Study (ODCS).

Carnitine deficiency is prevalent in patients undergoing hemodialysis, and it could result in lowered muscle strength. So far, the effect of treatment with levocarnitine on lower limb muscle strength has not been well described. This observational study examined the association between treatment with levocarnitine with the change in knee extensor strength (KES) in hemodialysis patients. Eligible patients were selected from the participants enrolled in a prospective cohort study for whom muscle strength was measured annually. We identified 104 eligible patients for this analysis. During the one-year period between 2014 to 2015, 67 patients were treated with intravenous levocarnitine (1000 mg per shot, thrice weekly), whereas 37 patients were not. The change in KES was significantly higher (p = 0.01) in the carnitine group [0.02 (0.01-0.04) kgf/kg] as compared to the non-carnitine group [-0.02 (-0.04 to 0.01) kgf/kg]. Multivariable-adjusted regression analysis showed the positive association between the change in KES and the treatment with levocarnitine remained significant after adjustment for the baseline KES and other potential confounders. Thus, treatment with intravenous levocarnitine was independently and positively associated with the change in KES among hemodialysis patients. Further clinical trials are needed to provide more solid evidence.

Protective effects of melatonin and L-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes.

The present study was designed to evaluate the possible protective effects of melatonin (MEL) and/or L-carnitine (L-CAR) against methotrexate (MTX)-induced toxicity in isolated rat hepatocytes. Hepatocytes were prepared using collagenase techniques of perfusion and digestion of rat liver. Trypan blue uptake, as well as, glutathione (GSH), lipid peroxidation (LPO), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α) levels were measured. Caspase-3 activity was also assessed. Pre-incubation of hepatocytes with MEL (1 mM) and/or L-CAR (10 mM) 30 min prior to intoxication with MTX, significantly protected hepatocytes against toxicity. In addition, LPO, NO, TNF-α levels, and caspase-3 activity were decreased in comparison to the MTX-intoxicated group. Furthermore, the two drugs increased the MTX-depleted GSH level. MEL and L-CAR prevented MTX-induced hepatocytotoxicity, at least partly, by their antioxidative, antiinflammatory, and antiapoptotic effects. Further studies are recommended on the clinical pharmacologic and toxicologic effects of MEL and L-CAR in patients receiving MTX.

The effects of L-carnitine on gastrointestinal contractility and histological changes in rat intestinal ischemia-reperfusion Injury / Efectos de la l-carnitina sobre la contractilidad gastrointestinal y los cambios histológicos en la lesión por isquemia-reperfusión intestinal de rata

SUMMARY: Ischemia-reperfusion (I/R) of the small intestine causes serious abdominal pathologies including tissue dysfunction and organ failure. L-carnitine (L-C), a powerful antioxidant, may help lessen the severity of these pathological effects since it plays a key role in energy metabolism. In this work we aimed to study the effects of L-C on the isolated ileal and duodenal contractility and histological changes in intestinal ischemia and reperfusion injury. Twenty eight Wistar rats were divided into four groups. The first group is the control group. Second group, I/R group, had rats submitted to 45-minutes of intestinal ischemia and to 45-minutes reperfusion. The third group, I/R+ L-C group, rats were treated with L-C 5 minutes before reperfusion and than submitted to ischemia. The fourth group, included rats that were treated with L-C without ischemia or reperfusion. Intestinal ischemia was conducted by obstructing superior mesentery arteries by silk loop. The ileal and duodenal segments were isolated and suspended in tissue bath. Contractile responses were induced by acetylcholine (Ach) and relaxation was achieved with phenylephrine. At the same time the terminal ileal and duodenal segments were examined for histological changes. Ach-induced contraction responses were higher in the I/R+L-C group, the L-C group, and the control group compared to the I/R group, in both ileal and duodenal segments. On the other hand, the phenylephrine-induced relaxations were higher in the I/R+L-C and L-C groups, especially in duodenal segments. In I/R group intestinal morphology was observed to be severely damaged whereas in I/R+L-C group the damage was noticeably lower possibly due to protective properties of L-C. I/R injury caused severe cellular damage response within the muscularis resulting in decreased gastrointestinal motility. Treatment with the L-C has significantly affected the gastrointestinal contractility. Also L-C treatment reduced the damage in intestinal morphology that occurs after IR injury.

RESUMEN: La isquemia-reperfusión (I/R) del intestino delgado provoca graves patologías abdominales que incluyen disfunción tisular y falla orgánica. La L-carnitina (L-C), un poderoso antioxidante, puede ayudar a disminuir la gravedad de estos efectos patológicos, ya que desempeña un papel clave en el metabolismo energético. El objetivo de este trabajo fue estudiar los efectos de L-C sobre la contractilidad ileal y duodenal aislada y los cambios histológicos en la lesión por isquemia y reperfusión intestinal. Se dividieron 28 ratas Wistar en cuatro grupos. El primer grupo fue el control. El segundo grupo, grupo I/R, de ratas sometidas durante 45 minutos de isquemia intestinal y a 45 minutos de reperfusión. El tercer grupo, grupo I/R+ L-C, las ratas se trataron con L-C, 5 minutos antes de la reperfusión y luego se sometieron a isquemia. El cuarto grupo, las ratas fueron tratadas con L-C sin isquemia ni reperfusión. La isquemia intestinal se realizó obstruyendo la arteria mesentérica superior con un asa de seda. Los segmentos ileal y duodenal se aislaron y suspendieron en un baño de tejido. Las respuestas contráctiles fueron inducidas por acetilcolina (Ach) y la relajación se logró con fenilefrina. Al mismo tiempo, se examinaron cambios histológicos de los segmentos del íleon terminal y del duodeno. Las respuestas de contracción inducidas por Ach fueron mayores en el grupo I/R+L-C, el grupo L-C y el grupo control en comparación con el grupo I/R, tanto en el segmento ileal como en el duodenal. Por otra parte, las relajaciones inducidas por fenilefrina fueron mayores en los grupos I/R+L-C y L-C, especialmente en los segmentos duodenales. En el grupo I/R se observó que la morfología intestinal estaba dañada significativamente, mientras que en el grupo I/R+L-C el daño fue notablemente menor, posiblemente debido a las propiedades protectoras de L-C. La lesión por I/R causó una respuesta de daño celular severo dentro de la capa muscular que resultó en una disminución de la motilidad gastrointestinal. El tratamiento con L-C afectó significativamente la contractilidad gastrointestinal. Por otra parte, el tratamiento L-C redujo el daño en la morfología intestinal que ocurre después de la lesión por IR.

Levocarnitine Supplementation Suppresses Lenvatinib-Related Sarcopenia in Hepatocellular Carcinoma Patients: Results of a Propensity Score Analysis.

This study investigated the inhibitory effect of levocarnitine supplementation on sarcopenia progression in hepatocellular carcinoma (HCC) patients treated with lenvatinib. We evaluated the skeletal muscle index (SMI). After propensity score matching for age, sex, modified albumin-bilirubin grade, baseline presence of sarcopenia, and branched-chain amino acid administration, we selected 17 patients who received levocarnitine supplementation after starting lenvatinib therapy and 17 propensity-score-matched patients who did not receive levocarnitine. Sarcopenia was present in 76% of the patients at baseline. Changes in baseline SMI at 6 and 12 weeks of treatment were significantly suppressed in the group with levocarnitine supplementation compared with those without (p = 0.009 and p = 0.018, respectively). While there were no significant differences in serum free carnitine levels in cases without levocarnitine supplementation between baseline and after 6 weeks of treatment (p = 0.193), free carnitine levels were significantly higher after 6 weeks of treatment compared with baseline in cases with levocarnitine supplementation (p < 0.001). Baseline SMI and changes in baseline SMI after 6 weeks of treatment were significantly correlated with free carnitine levels (r = 0.359, p = 0.037; and r = 0.345, p = 0.045, respectively). Levocarnitine supplementation can suppress sarcopenia progression during lenvatinib therapy.

A Pilot, Phase II, Observational, Case-Control, 1-Month Study on Asthenopia in Video Terminal Operators without Dry Eye: Contrast Sensitivity and Quality of Life before and after the Oral Consumption of a Fixed Combination of Zinc, L-Carnitine, Extract of Elderberry, Currant and Extract of Eleutherococcus.

The aims of the study were to investigate the ability and effectiveness of an oral intake of a fixed combination of zinc, L-carnitine, elderberry extract, black currant and Eleutherococcus extract in controlling the symptoms of eyestrain in videoterminal (VDT) users and to record its effects on contrast sensitivity. A single-center, phase II, observational, case-control, 1-month study in VDT workers without dry eye disease was carried out. Demographics and number of actual hours at VDT/day were taken into account. All subjects underwent a complete ophthalmic examination, including assessment of contrast sensitivity, and completed the computer vision symptom scale questionnaire at baseline and one month later. A total of 30 Caucasian subjects adhered to the required inclusion criteria and completed the study; 15 subjects were treated (T) and 15 were controls (C). All clinical data at baseline were similar in both groups (p > 0.05): after one month, all subjects had stable visual acuity, refractive defect and intraocular pressure (IOP); screen exposure time was unchanged. Regarding symptoms, at randomization, the groups had a similar score: 33.1 ± 3.3 in T and 32.8 ± 5.6 in C. One month later, the computer vision symptom scale (CVSS) questionnaire score decreased by -14.1 ± 3, 1 (p = 0.000) and -2.3 ± 1.8 (p = 0.568), respectively. Regarding contrast sensitivity, in group C the values of spatial frequencies remained unchanged, while they improved in almost all the cycles per degree stimuli in the treated group. Oral intake of a fixed combination of zinc, L-carnitine, elderberry extract, black currant and eleutherococcus extract can significantly improve contrast sensitivity and symptoms in VDT workers with no signs of dry eye disease.

Effect of Acute and Chronic Oral l-Carnitine Supplementation on Exercise Performance Based on the Exercise Intensity: A Systematic Review.

l-Carnitine (l-C) and any of its forms (glycine-propionyl l-Carnitine (GPL-C) or l-Carnitine l-tartrate (l-CLT)) has been frequently recommended as a supplement to improve sports performance due to, among others, its role in fat metabolism and in maintaining the mitochondrial acetyl-CoA/CoA ratio. The main aim of the present systematic review was to determine the effects of oral l-C supplementation on moderate- (50-79% V˙O2 max) and high-intensity (≥80% V˙O2 max) exercise performance and to show the effective doses and ideal timing of its intake. A structured search was performed according to the PRISMA® statement and the PICOS guidelines in the Web of Science (WOS) and Scopus databases, including selected data obtained up to 24 October 2021. The search included studies where l-C or glycine-propionyl l-Carnitine (GPL-C) supplementation was compared with a placebo in an identical situation and tested its effects on high and/or low-moderate performance. The trials that used the supplementation of l-C together with additional supplements were eliminated. There were no applied filters on physical fitness level, race, or age of the participants. The methodological quality of studies was evaluated by the McMaster Critical Review Form. Of the 220 articles obtained, 11 were finally included in this systematic review. Six studies used l-C, while three studies used l-CLT, and two others combined the molecule propionyl l-Carnitine (PL-C) with GPL-C. Five studies analyzed chronic supplementation (4-24 weeks) and six studies used an acute administration (<7 days). The administration doses in this chronic supplementation varied from 1 to 3 g/day; in acute supplementation, oral l-C supplementation doses ranged from 3 to 4 g. On the one hand, the effects of oral l-C supplementation on high-intensity exercise performance variables were analyzed in nine studies. Four of them measured the effects of chronic supplementation (lower rating of perceived exertion (RPE) after 30 min at 80% V˙O2 max on cycle ergometer and higher work capacity in "all-out" tests, peak power in a Wingate test, and the number of repetitions and volume lifted in leg press exercises), and five studies analyzed the effects of acute supplementation (lower RPE after graded exercise test on the treadmill until exhaustion and higher peak and average power in the Wingate cycle ergometer test). On the other hand, the effects of l-C supplementation on moderate exercise performance variables were observed in six studies. Out of those, three measured the effect of an acute supplementation, and three described the effect of a chronic supplementation, but no significant improvements on performance were found. In summary, l-C supplementation with 3 to 4 g ingested between 60 and 90 min before testing or 2 to 2.72 g/day for 9 to 24 weeks improved high-intensity exercise performance. However, chronic or acute l-C or GPL-C supplementation did not present improvements on moderate exercise performance.

Suitable ratio of dietary L-carnitine and α-ketoglutarate improves growth and health performance in Nile tilapia, Oreochromis niloticus.

L-carnitine (LC) and α-Ketoglutarate (AKG) are important growth promoters used in aquafeed. The study aimed to evaluate the incorporation of LC and AKG at different ratios in the diet of tilapia (initial weight 1.38 ± 0.03 g) in order to facilitate lipid utilization and protein synthesis. Fish were fed six isonitrogenous (~ 30 g/100 g CP) and isolipidic (~ 6 g/100 g CL) diets containing graded LC/AKG ratios of 0 (Control), 0.11, 0.42, 1.00, 2.33 and 9.00 in six treatments for 60 days. Fish fed with LC/AKG ratios 2.33 and 9.00 showed significantly (P < 0.05) higher percentage weight gain, specific growth rate and protein efficiency ratio. Feed conversion ratio in fish-fed diets with LC/AKG ratio 9.00 improved significantly (p < 0.05) than other treatments. The whole-body protein content of tilapia and digestive enzyme activity were significantly higher with higher weight gain. The body lipid content was significantly lower in the LC/AKG ratio 9.00. The liver antioxidant parameters and activity of the immune components were significantly higher in the LC/AKG ratio 9 group. The lower serum triglyceride and cholesterol level was also recorded in LC/AKG ratio 9 group. The histology of the intestine and liver showed increased villi area and decreased lipid droplets, respectively, in tilapia fed with higher LC/AKG ratios. It was concluded from the above results that the higher LC and lower AKG (LC/AKG ratio 9.00) combination attributed maximum lipid utilization and higher protein efficiency and thus better growth performance in tilapia. This was also reflected in activity of digestive enzymes, antioxidant enzymes and immune status in tilapia.

L-Carnitine Tartrate Supplementation for 5 Weeks Improves Exercise Recovery in Men and Women: A Randomized, Double-Blind, Placebo-Controlled Trial.

L-carnitine tartrate has been shown to improve relatively short-term recovery among athletes. However, there is a lack of research on the longer-term effects in the general population. OBJECTIVE: The primary objectives of this randomized double-blind, placebo-controlled trial were to evaluate the effects of daily L-carnitine tartrate supplementation for 5 weeks on recovery and fatigue. METHOD: In this study, eighty participants, 21- to 65-years-old, were recruited. Participants were split into two groups of forty participants each, a placebo, and a L-carnitine Tartrate group. Seventy-three participants completed a maintenance exercise training program that culminated in a high-volume exercise challenge. RESULTS: Compared to placebo, L-carnitine tartrate supplementation was able to improve perceived recovery and soreness (p = 0.021), and lower serum creatine kinase (p = 0.016). In addition, L-carnitine tartrate supplementation was able to blunt declines in strength and power compared to placebo following an exercise challenge. Two sub-analyses indicated that these results were independent of gender and age. Interestingly, serum superoxide dismutase levels increased significantly among those supplementing with L-carnitine tartrate. CONCLUSIONS: These findings agree with previous observations among healthy adult subjects and demonstrate that L-carnitine tartrate supplementation beyond 35 days is beneficial for improving recovery and reducing fatigue following exercise across gender and age.

Pathobiological Relationship of Excessive Dietary Intake of Choline/L-Carnitine: A TMAO Precursor-Associated Aggravation in Heart Failure in Sarcopenic Patients.

The microecological environment of the gastrointestinal tract is altered if there is an imbalance between the gut microbiota phylases, resulting in a variety of diseases. Moreover, progressive age not only slows down physical activity but also reduces the fat metabolism pathway, which may lead to a reduction in the variety of bacterial strains and bacteroidetes' abundance, promoting firmicutes and proteobacteria growth. As a result, dysbiosis reduces physiological adaptability, boosts inflammatory markers, generates ROS, and induces the destruction of free radical macromolecules, leading to sarcopenia in older patients. Research conducted at various levels indicates that the microbiota of the gut is involved in pathogenesis and can be considered as the causative agent of several cardiovascular diseases. Local and systematic inflammatory reactions are caused in patients with heart failure, as ischemia and edema are caused by splanchnic hypoperfusion and enable both bacterial metabolites and bacteria translocation to enter from an intestinal barrier, which is already weakened, to the blood circulation. Multiple diseases, such as HF, include healthy microbe-derived metabolites. These key findings demonstrate that the gut microbiota modulates the host's metabolism, either specifically or indirectly, by generating multiple metabolites. Currently, the real procedures that are an analogy to the symptoms in cardiac pathologies, such as cardiac mass dysfunctions and modifications, are investigated at a minimum level in older patients. Thus, the purpose of this review is to summarize the existing knowledge about a particular diet, including trimethylamine, which usually seems to be effective for the improvement of cardiac and skeletal muscle, such as choline and L-carnitine, which may aggravate the HF process in sarcopenic patients.

Inhibition of neutral sphingomyelinase 2 reduces extracellular vesicle release from neurons, oligodendrocytes, and activated microglial cells following acute brain injury.

Extracellular Vesicles (EVs) are implicated in the spread of pathogenic proteinsin a growing number of neurological diseases. Given this, there is rising interest in developing inhibitors of Neutral Sphingomyelinase 2 (nSMase2), an enzyme critical in EV biogenesis. Our group recently discovered phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate (PDDC), the first potent, selective, orally-available, and brain-penetrable nSMase2 inhibitor, capable of dose-dependently reducing EVs release in vitro and in vivo. Herein, using multiplexed Surface Plasmon Resonance imaging (SPRi), we evaluated which brain cell-derived EVs were affected by PDDC following acute brain injury. Mice were fed PDDC-containing chow at doses which gave steady PDDC brain exposures exceeding its nSMase2 IC50. Mice were then administered an intra-striatal IL-1ß injection and two hours later plasma and brain were collected. IL-1ß injection significantly increased striatal nSMase2 activity which was completely normalized by PDDC. Using SPRi, we found that IL-1ß-induced injury selectively increased plasma levels of CD171 + and PLP1 + EVs; this EV increase was normalized by PDDC. In contrast, GLAST1 + EVs were unchanged by IL-1ß or PDDC. IL-1ß injection selectively increased EVs released from activated versus non-activated microglia, indicated by the CD11b+/IB4 + ratio. The increase in EVs from CD11b + microglia was dramatically attenuated with PDDC. Taken together, our data demonstrate that following acute injury, brain nSMase2 activity is elevated. EVs released from neurons, oligodendrocytes, and activated microglial are increased in plasma and inhibition of nSMase2 with PDDC reduced these IL-1ß-induced changes implicating nSMase2 inhibition as a therapeutic target for acute brain injury.

Chlorogenic acid inhibits trimethylamine-N-oxide formation and remodels intestinal microbiota to alleviate liver dysfunction in high L-carnitine feeding mice.

High L-carnitine ingestion has been shown to cause liver injury, mechanically due to an elevated circulating level of trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite from L-carnitine. This study aimed to investigate whether chlorogenic acid (CGA), a health-promoting polyphenol, could inhibit TMAO formation and thereafter might prevent L-carnitine-induced liver injury in mice. Feeding of mice with 3% L-carnitine in drinking water increased the serum and urinary levels of TMAO (p < 0.01 vs. Normal), whereas the serum and urinary TMAO formation was sharply reduced by CGA administration (p < 0.01). At the phylum level, CGA inhibited the L-carnitine-induced increase in the abundance of Firmicutes and Proteobacteria, while it promoted Bacteroidetes. At the genus level, CGA notably increased the abundance of Akkermansia and Bacteroides, but reduced the population of Erysipelatoclostridium, Faecalibaculum and Erysipelotrichaceae in high L-carnitine feeding mice. Meanwhile, CGA caused strong inhibition against the increase of liver injury markers (i.e. AST, ALT and ALP), hepatic inflammatory cytokines (i.e. IL-1, IL-6, TNF-α and TNF-ß) and dyslipidemia (i.e. TC, TG, LDL-C and HDL-C) in L-carnitine-fed mice (p < 0.05). These findings suggest that CGA holds great potential to alleviate liver dysfunction induced by high L-carnitine ingestion. The beneficial effect might be attributed to the protection against TMAO formation and the improvement of the health-promoting gut microbiota, as well as the antioxidant and anti-inflammatory properties of CGA.

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 1 H-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.

Topical Delivery of Levocarnitine to the Cornea and Anterior Eye by Thermosensitive in-situ Gel for Dry Eye Disease.

PURPOSE: To prepare the levocarnitine thermosensitive in situ gel (LCTG) and evaluate its effect on dry eye disease (DED). METHODS: Draize eye irritation test and other examinations were used to evaluate the eye irritation after multiple administration of LCTG. The Schirmer test, fluorescein sodium staining, HE staining and TUNEL staining were used to detect the tear secretion, corneal injury, histopathological changes of the cornea and lacrimal gland, and the apoptosis rate of cornea epithelial cells after 3 days of the administration. The conjunctival goblet cell density was detected by PAS staining, and the expression levels of matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-9 (MMP-9) of corneal epithelial cells were detected by immunofluorescence staining after 7 days of the administration. RESULTS: LCTG is non-irritating to rabbit eyes and has good biocompatibility. LCTG administration for 3 days can significantly increase the amount of tear secretion in mice with DED, promote corneal epithelial integrity and central corneal epithelium thickness recovery, and improve the pathological morphology and structure of corneal and lacrimal gland tissues, and reduce the apoptosis rate of the corneal epithelial cells. After 7 days of the administration, the preparation can promote the proliferation of conjunctival goblet cells and down-regulate the cornea expression levels of MMP-3 and MMP-9 in epithelial cells. CONCLUSION: The LCTG has a good curative effect on mice with DED, and the overall curative effect is better than that of levocarnitine solution.

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Effects of Reducing L-Carnitine Supplementation on Carnitine Kinetics and Cardiac Function in Hemodialysis Patients: A Multicenter, Single-Blind, Placebo-Controlled, Randomized Clinical Trial.

L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (ß = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.

Effect of l-carnitine supplementation on children and adolescents with nonalcoholic fatty liver disease (NAFLD): a randomized, triple-blind, placebo-controlled clinical trial.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the pediatric population at global level. Present study aims to assess the effect of l-carnitine supplementation on the NAFLD in children and adolescents. METHODS: This randomized, triple-blind, placebo-controlled clinical trial was conducted in 2018-2019. Study was carried out in NAFLD participants (5-15 years). They were randomly assigned to receive either 50 mg/kg/day l-carnitine twice a day or identical placebo per day for three months. Liver enzymes and liver ultrasonography were assessed before and after the intervention. Both groups received similar consultation for lifestyle changes. RESULTS: Overall, 55 participants completed the study, 30 patients in the l-carnitine group and 25 patients in placebo group. Mean changes of anthropometric measurements did not have significant differences between groups (p>0.05). No significant differences in the mean changes of aspartate aminotransferase (AST) (p=0.82) and alanine aminotransferase (ALT) (p=0.76) levels were documented between two groups. Based on within-group analysis, there were significant changes in AST and ALT levels before and after the intervention in both groups. The sonographic grades of fatty liver were not significantly different between two groups before (p=0.94) and after intervention (p=0.93). CONCLUSIONS: In the present clinical trial, L-carnitine did not have significant effect on improving biochemical and sonographic markers of NAFLD in children and adolescents. Future studies are necessary to evaluate the applicability and efficacy of long-term l-carnitine supplementation to treatment of NAFLD in pediatric population. TRIAL REGISTRATION: IRCT20170628034786N2.

Quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.

OBJECTIVES: This study aimed to explore the quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients using model-based meta-analysis (MBMA). METHODS: Literatures were retrieved from the public database and data from these trials were extracted. The quantitative efficacy of L-carnitine on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients were evaluated by maximal effect (Emax) models with nonlinear mixed effects modeling (NONMEM). RESULTS: In the model of FPG, Emax and treatment duration to reach half of the maximal effects (ET50) were -9.8% and 36.1 weeks, respectively. In the model of HbA1c, Emax and ET50 were -19.6% and 106 weeks, respectively. In addition, the durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on FPG were 13, 36.1, 118, 160, and 390 weeks, respectively. The durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on HbA1c were 38, 106, 334, 449, and 1058 weeks, respectively. CONCLUSIONS: It was the first time to provide valuable quantitative information for efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.

Possible Neuroprotective Effects of l-Carnitine on White-Matter Microstructural Damage and Cognitive Decline in Hemodialysis Patients.

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.

L-Carnitine Tartrate Downregulates the ACE2 Receptor and Limits SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection.