A prospective study to evaluate the efficacy and safety of vitamin E and levocarnitine prophylaxis against doxorubicin-induced cardiotoxicity in adult breast cancer patients.

BACKGROUND: Doxorubicin induces acute and chronic cardiotoxicity. This study is aimed to evaluate the efficacy and safety of vitamin E and levocarnitine (EL) as cardioprotective agents against acute doxorubicin cardiotoxicity in female adult breast cancer patients. METHODS: A prospective, randomized controlled study was conducted in patients treated with doxorubicin and cyclophosphamide (AC). Patients were randomly assigned to EL plus AC or AC alone for the duration of 4 cycles. Cardiac enzymes (B-type natriuretic peptide, creatine kinase, troponin I (Trop)) and cardiac events were monitored during treatment to evaluate the cardioprotective efficacy of EL. RESULTS: Seventy-four patients were recruited and received four cycles of chemotherapy. The intervention group (n = 35) showed a significant reduction in both the B-type natriuretic peptide and creatine kinase cardiac enzymes compared to the control group (n = 39). The median (IQR) change for BNP was 0.80 (0.00-4.00) for IG versus 1.80 (0.40-3.60) for CG groups (p < 0.001); creatine kinase was -0.08 (-0.25-0.05) for IG versus 0.20 (0.05-0.50) for CG (p < 0.001). The addition of EL decreased the cardiac events by 24.2% (p = 0.02). All adverse events were tolerable and manageable. CONCLUSION: This study supports the addition of EL as prophylaxis against acute doxorubicin cardiotoxicity and it was also very well tolerated by a majority of the patients. The co-administration of EL at higher doxorubicin (240 mg/m2) dose should be further investigated.

Estimation of L-carnitine levels in diabetic completely edentulous patients for implant diagnosis: A cross-sectional study.

Background: Carnitine is effective in preventing the accumulation of end products related to lipid peroxidation due to its anti-inflammatory and antioxidant effects. Carnitine also exerts a significant anti-inflammatory role through the downregulation of the nuclear factor kappa beta pathway, which leads to a decrease in the expression of pro-inflammatory cytokines.The aim of the study was to estimate the L-carnitine (L-C) levels in diabetic completely edentulous patients. Materials and Methods: A cross-sectional study was conducted after the selection of 60 samples based on the inclusion and exclusion criteria. The collected saliva samples were utilized to measure the levels of L-C using the sandwich enzyme-linked immunosorbent assay (ELISA) method. One hundred microliters of sample was applied to a particular row of wells and incubated for an hour as part of the sandwich ELISA procedure. After the wells had been cleaned, a second batch of monoclonal L-C was added, and they were once more incubated for an hour. The horseradish peroxidase substrate was then applied after washing the second batch as well. To allow the blue-to-yellow color transition, the wells were kept steady. Following the observation of the color shift, the OD was measured, and the concentration was determined using the sandwich ELISA kit's standard curve as an intercept. The data were statistically analyzed using the independent t-test (significant level P < 0.05) and were tabulated. Results: The L-C levels have higher levels in nondiabetic patients than in diabetic patients. The difference in the baseline mean value between the groups was statistically significant (P = 0.00). Although it is statistically significant (P = 0.00), the mean value for diabetic individuals is 0.19 as opposed to 0.29 for nondiabetic patients. Conclusion: Based on the findings, it can be concluded that L-C improves insulin sensitivity and glucose disposal in diabetic completely edentulous patients.

Muscle Cramps in Outpatients with Liver Diseases in Tokyo, Japan.

Background and Objectives: Muscle cramps are often observed in patients with liver diseases, especially advanced liver fibrosis. The exact prevalence of muscle cramps in outpatients with liver diseases in Japan is unknown. Patients and Methods: This study examined the prevalence of, and therapies for, muscle cramps in outpatients with liver diseases in Tokyo, Japan. A total of 238 outpatients with liver diseases were retrospectively examined. We investigated whether they had muscle cramps using a visual analog scale (VAS) (from 0, none, to 10, strongest), and also investigated their therapies. Results: Muscle cramps were observed in 34 outpatients with liver diseases (14.3%); their mean VAS score was 5.53. A multivariate analysis demonstrated that older age (equal to or older than 66 years) was the only significant factor as-sociated with muscle cramps. The prevalence of muscle cramps among patients with liver diseases seemed not to be higher. The problem was that only 11 (32.4%) of 34 outpatients received therapy for their muscle cramps. Conclusions: Only age is related to muscle cramps, which is rather weak, and it is possible that this common symptom may not be limited to liver disease patients.

Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1.

This study aimed to explore the effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) on levocarnitine (LC)-mediated regulation of angiotensin II (AngII)-induced myocardial fibrosis (MF) and its underlying mechanisms. H9C2 cells were treated with AngII for 24 h to induce fibrosis. The cells were then treated with LC or transfected with TIMP-1-OE plasmid/si­TIMP-1. Cell apoptosis, viability, migration, and related gene expression were analyzed. AngII treatment significantly upregulated Axl, α-SMA, and MMP3 expression (P < 0.05) and downregulated STAT4 and TIMP1 expression (P < 0.05) relative to the control levels. After transfection, cells with TIMP-1 overexpression/knockdown were successfully established. Compared with that of the control, AngII significantly inhibited cell viability and cell migration while promoting cell apoptosis (P < 0.05). LC and TIMP-1-OE transfection further suppressed cell viability and migration induced by Ang II and upregulated apoptosis, whereas si-TIMP-1 had the opposite effect. Furthermore, LC and TIMP-1-OE transfection downregulated Axl, AT1R, α-SMA, collagen III, Bcl-2, and MMP3 expression caused by AngII and upregulated caspase 3, p53, and STAT4 expression, whereas si-TIMP-1 had the opposite effect. TIMP-1 is therefore a potential therapeutic target for delaying MF progression.

[Exploring the mechanism of levocarnitine in the treatment of epididymitis based on network pharmacology and molecular docking technology].

OBJECTIVE: To explore the potential mechanism of action of levocarnitine in the treatment of epididymitis based on network pharmacology and experimental research. METHODS: The target proteins related to epididymitis and levocarnitine were retrieved through multiple databases, and the common targets were obtained using Venny software. The protein-protein interactions were obtained using the STRING database. Cytoscape software was used for visualization, and key targets were selected after topological analysis. GO and KEGG pathway enrichment analysis was performed using the DAVID database. Molecular docking was performed using Autodock Vina. RESULTS: A total of 130 drug targets and 2 151 disease targets were obtained, with 47 common targets. Protein-protein interaction network analysis identified core targets of levocarnitine in the treatment of epididymitis, including AKT1, HSP90AA1, ALB, CASP3, GSK3B, and GSR. KEGG pathway analysis suggested that metabolic pathways, lipid metabolism and atherosclerosis, cancer pathways, fluid shear stress and atherosclerosis, measles, chemical carcinogens-reactive oxygen species, purine metabolism, PI3K-Akt, and other signaling pathways may be associated with the mechanism of levocarnitine in the treatment of epididymitis. CONCLUSION: This study revealed through network pharmacology that levocarnitine may act on multiple signaling pathways by targeting AKT1, HSP90AA1, ALB, CASP3, GSK3B, GSR, etc., thereby potentially exerting therapeutic effects on epididymitis.

[Antiastenic effect of sequential levocarnitine and acetylcarnitine therapy in patients with cardiovascular diseases]. / Antiastenicheskii effekt posledovatel'noi terapii levokarnitinom i atsetilkarnitinom patsientov s serdechno-sosudistoi patologiei.

OBJECTIVE: Evaluation of the antiasthenic effect of sequential therapy with levocarnitine (LC) and acetylcarnitine (ALC) in patients with arterial hypertension and/or ischemic heart disease (CHD) with asthenic syndrome (AS). MATERIAL AND METHODS: An open comparative study included 120 patients aged 54-67 years in patients with arterial hypertension and/or coronary artery disease with AS. Patients of group1 (n=60), in addition to basic therapy for the underlying disease, received LC (Elcar solution for intravenous and intramuscular injection of 100 mg/ml, the company PIQ-PHARMA) intravenously for 10 days at a dose of 1000 mg/day, followed by a transition to oral administration of ALC (Carnicetine, the company PIQ-PHARMA) 500 mg (2 capsules) 2 times a day for 2 months. Group2 patients (n=60) received only basic therapy for major diseases. The duration of observation was 70 days. The severity of AS was assessed using the MFI-20 questionnaire (MultidiMensional Fatigue Inventory) and the visual analog scale VAS-A (Visual Analog Scale Measuring fatigue). RESULTS: In patients of group1, a statistically significant decrease in various manifestations of AS was noted. The differences were significant both in comparison with the baseline level and in comparison with the 2nd group. The endothelium-protective effect of LC and ALC has been established. CONCLUSION: The results obtained indicate that in such comorbid patients, the use of LC and ALC reduces the severity of AS manifestations, and the established endotheliotropic properties of the drugs allow them to be recommended as part of the complex personalized therapy of patients with cardiovascular diseases.

The Roles of Antidotes in Emergency Situations.

Management of the acutely poisoned patient requires supportive care and timely administration of antidotes to minimize ongoing toxicity and mortality. New applications for old antidotes include utilization of methylene blue and hydroxocobalamin in vasoplegia. Fomepizole is also being evaluated as a potential adjunct in acetaminophen toxicity. Other advancements include individualized acetylcysteine dosing regimens for acetaminophen toxicity and carnitine supplementation in valproic acid toxicity. Additional antidote considerations include administration of lipid emulsion in lipophilic xenobiotic exposure not responsive to standard resuscitative modalities. These expert recommendations provide guidance for providers caring for the acutely poisoned patient.

Vitamin E and levocarnitine as prophylaxis against doxorubicin-induced cardio toxicity in the adult cancer patient: A review.

OBJECTIVE: Doxorubicin, a component of the anthracycline group, is a highly effective in the treatment of hematologic and solid malignancies. Because of the cardiotoxic adverse effects, use is limited. Antioxidants may negate this anthracycline-induced cardiotoxicity, although the literature is not conclusive with regards to the cardioprotective benefits of antioxidants. This review assessed and mapped evidence of the efficacy of vitamin E and levocarnitine against doxorubicin-induced cardiotoxicity in adult cancer patients. DATA SOURCES: This review was based on the Arksey and O'Malley methodology. Potentially relevant literature in English published between January 1960 and April 2021 was identified through a database search. Oxford Quality Scoring System and AMSTR2 were used to assess the quality of trials and systematic reviews respectively, as well as the risks of potential bias. DATA SUMMARY: Nineteen of the 10 268 (0.2%) articles from the initial search were included in the final analysis (12 clinical trials and 7 systematic reviews). Vitamin E was included in seven prospective clinical trials. Levocarnitine was included in five clinical trials as an individual agent and a single trial as a combination treatment. No trials could be found investigating the combination of vitamin E and levocarnitine in humans. CONCLUSIONS: This review found that levocarnitine trials showed some cardioprotective effects but the results from vitamin E trials were controversial and inconclusive. Most of the trials reviewed had some shortcomings. Further investigations are therefore needed to determine the efficacy of vitamin E and levocarnitine in preventing doxorubicin-induced cardiotoxicity in adult cancer patients.

The mechanism analysis using PI3K/AKT pathway for the effects of levocarnitine in the treatment of spermatogenic dysfunction.

LEV improves the percentage of forward-motion spermatozoon and total sperm motility in patients with oligozoospermia or asthenospermia in clinical settings. However, the mechanism of action of levocarnitine (LEV) in the treatment of spermatogenic dysfunction was unclear. Based on in vitro and in vivo experiments, we used Glucosides of Tripterygium wilfordii Hook F (GTW) to construct a cell model (using spermatogenic GC-1 spg cells) and an animal model (using rats) of spermatogenic dysfunction. LEV and LY294002 (a PI3K pathway inhibitor) were then administered. By assessing apoptosis and sperm quality and motility, the underlying mechanism was explored. We found that GTW induced spermatogenic dysfunction, and LEV ameliorated the GTW-induced spermatogenic dysfunction. LEV inhibited GC-1 spg cell apoptosis and improved the sperm count and percentages of PR (forward motion) + NP (non-forward motion) (p < .01). Besides, the morphology of testicular tissue in the GTW + LEV and LY + LEV groups was superior to that in the GTW group. We can to the conclusion that LEV may operate via the PI3K/AKT signalling pathway, with increases in PI3K, p-AKT, and BCL-2 protein and mRNA expression, so that the percentages of GC-1 spg cells apoptosis decrease, and the sperm count and motility improve.

Therapeutic Effects of Levocarnitine or Vitamin B Complex and E With Selenium on Glycerin-Treated Holstein Friesian Cows With Clinical Ketosis.

Currently, ketosis has no fully satisfactory resolution in dairy cows. Here, we investigated the effect of levocarnitine or vitamin B complex and E with selenium on clinically ketotic cows (ß-hydroxybutyrate ≥ 3.0 mmol/L and decreased milk yield), fed glycerin. In total, 18 cases of Holstein cows with clinical ketosis during the postpartum transition period were randomly assigned to three treatments (6 cases per group): (1) levocarnitine (C+G), (2) vitamin B complex and E with selenium (VBES+G), and (3) levocarnitine and vitamin B complex and E with selenium (C+VBES+G). All groups were administered glycerin. Treatments were administered daily for 4 days. Blood sampling was performed on the onset day of ketosis (day 0), day 4, and day 6. ß-Hydroxybutyrate (BHBA), milk yield (MY), and serum biochemical values were measured. Half of the animals in C+G failed to overcome clinical ketosis. VBES+G treatment ameliorated BHBA (p < 0.05), MY, and glucose on day 4. However, ketosis was exacerbated following the discontinuation of the treatment. C+VBES+G treatment improved BHBA, glucose (p < 0.05), and MY and reduced ketotic cases on days 4 and 6 with greater improvements compared to the others. In conclusion, combined treatment with levocarnitine, vitamin B complex and E with selenium, and glycerin may have the therapeutic effect on clinical ketosis.

Evaluation of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients.

INTRODUCTION: Critically ill patients treated with valproic acid are at risk for hyperammonemic encephalopathy. Both levocarnitine and lactulose, either alone or in combination, have been used for the treatment of hyperammonemia associated with valproic acid, however they have not been directly compared in the literature. The aim of this study was to compare the effect of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients. METHODS: This was a retrospective, system-wide, cohort study of critically ill patients who received valproic acid and levocarnitine, lactulose, or combination therapy from January 1, 2012 to October 31, 2019. The primary outcome of the study was the change in ammonia level from baseline to the lowest point within the first 48 h of treatment. Secondary outcomes included the change in ammonia levels within the first 7 days, the incidence of a clinically significant reduction, ICU length of stay, hospital length of stay, and hospital mortality. RESULTS: A total of 371 charts were reviewed and 114 patients (levocarnitine [n = 15], lactulose [n = 72], and combination [n = 27]) were included. No difference in the primary outcome was observed (levocarnitine [11umol/L] vs. lactulose [20 umol/L] vs. combination [23 umol/L], p = 0.605). The incidence of a clinically significant reduction in ammonia levels at 48 h did not differ between groups, nor did mortality. CONCLUSION: In critically ill patients with valproic acid-induced hyperammonemia, there was no significant difference in the reduction in ammonia levels in the first 48 h of treatment between levocarnitine, lactulose, and combination therapy.

The Efficacy of Levocarnitine Treatment in Relieving Fatigue in Patients with Cirrhosis but without Overt Hepatic Encephalopathy.

Objective In the present study, we prospectively examined the efficacy of levocarnitine in relieving symptoms of fatigue in patients with cirrhosis but without overt hepatic encephalopathy. Methods Twenty-one cirrhotic patients who were able to undergo fatigue symptom evaluations at our institution were enrolled. A total of 12 cirrhotic patients underwent levocarnitine treatment (1,200-1,800 mg/day), while 9 did not undergo levocarnitine treatment. As primary endpoints, we investigated whether or not levocarnitine treatment exerted any beneficial effects by assessing the symptoms of fatigue [8-item Short-Form Health Survey (SF-8) and Fisk Fatigue Severity Score (FFSS)] at baseline and three months after treatment. Furthermore, as exploratory secondary endpoints, we investigated whether or not levocarnitine treatment exerted ameliorative effects on oxidative stress by assessing the serum thioredoxin (TRX) and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Results The median age of the patients was 73 years old. Three men and 18 women were categorized by their Child-Pugh class (A and B in 14 and 7 patients, respectively). There were no significant differences in the clinical laboratory values between the two groups. The FFSS and SF-8 scores were significantly improved in the patients with cirrhosis who underwent levocarnitine treatment (p<0.01) but not in those who did not undergo levocarnitine treatment. Furthermore, three months after levocarnitine treatment, the serum carnitine concentrations were significantly increased, and the serum thioredoxin levels were decreased in the patients with cirrhosis who underwent levocarnitine treatment (p<0.05). Conclusion These results suggest that levocarnitine treatment may relieve symptoms of fatigue in cirrhotic patients by reducing oxidative stress.

[Possibilities of sequential levocarnitin and acetylcarnitin treatment in correcting cognitive deficiency in patients with cardiovascular diseases]. / Vozmozhnosti posledovatel'noi terapii levokarnitinom i atsetilkarnitinom v korrektsii kognitivnogo defitsita u patsientov s serdechno-sosudistoi patologiei.

OBJECTIVE: To evaluate the effectiveness of sequential therapy with levocarnitine and acetylcarnitine in patients with cardiovascular pathology (arterial hypertension and/or coronary heart disease) and moderate cognitive deficits. MATERIAL AND METHODS: The study included 120 patients aged 54-67 years. The main group of patients (n=60) in addition to the basic treatment of the underlying disease received l-carnitine (Elkar solution for intravenous and intramuscular injection of 100 mg/ml, the company «PIK-FARMA¼)/jet during 10 days in a dose of 1000 mg/day, with following transition to oral administration of acetyl-l-carnitine (Carnitin, the company «PIK-FARMA¼), 500 mg (2 cap Sula) 2 times a day for 2 months. The comparison group (n=60) received basic therapy for major diseases. The total duration of follow-up was 70 days. RESULTS: The results obtained indicate that in such comorbid patients, the use of levocarnitine and acetylcarnitine reduces the severity of cognitive deficits. An important aspect of their pathogenetic effect on the severity of cognitive deficits may be the possibility of correcting endothelial dysfunction. The use of levocarnitine and acetylcarnitine in patients with cardiovascular pathology has demonstrated good tolerability and safety.

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.

Analysis of the efficacy of torasemide combined with levocarnitine in the treatment of chronic heart failure / 中国临床药理学与治疗学

AIM: To explore the efficacy of torasemide combined with levocarnitine in the treatment of chronic heart failure (CHF). METHODS: From July 2018 to July 2020, 75 patients with CHF were recruited and randomly assigned into the control group (37 cases) and the study group (38 cases) according to the random number table method. The control and study groups were treated with levocarnitine and the combination of levocarnitine and torasemide, respectively. The clinical efficacy of the two groups was evaluated. The ventricular remodeling indexes and 6-minute walk test (6MWT) distance were compared between the two groups before and after treatment. The serum levels of serum galectin-3 (Gal-3), interleukin-33 (IL-33), hypersensitive C-reactive protein (hs-CRP), and the plasma concentrations of N terminal pro B type natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) were determined. RESULTS: (1) After treatment, the total clinical effective rate of the study group (92.11%) was higher than that of the control group (72.97%) (P<0.05). (2) The diastolic interventricular septal thickness (IVST) and diastolic left ventricular posterior wall thickness (LVPWT) were decreased following the treatment in both groups (P<0.05), whereas the treatment led to the increases of the left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) in both groups (P<0.05). Compared with those in the control group, IVST and LVPWT in the study group were lower (P<0.05), and LVMI and LVEF were higher (P<0.05). (3) The levels of serum Gal-3, IL-33 and hs-CRP in the two groups were decreased after treatment (P<0.05); compared with those in the control group, the levels of serum Gal-3, IL-33 and hs-CRP were reduced to a greater extent in the study group (P<0.05). (4) Compared with that before treatment, 6MWT distance in both groups increased after treatment (P<0.05); the improvement in the study group was more significant relative to those in the control group (P<0.05). (5) Compared with before treatment, the expression levels of plasma NT-proBNP and BNP in the two groups were decreased after treatment (P<0.05); the reduction of plasma NT-proBNP and BNP levels in the study group was greater than the control group (P<0.05). CONCLUSION: Torasemide combined with levocarnitine is more effective than levocarnitine monotherapy in the treatment of CHF and can significantly improve ventricular remodeling index and motor function, reduce serum inflammation, and enhance cardiac function with definite curative effect.

Clinical study of Roxastat combined with levocarnitine and polysaccharide iron complex in patients with chronic renal failure hemodialysis anemia / 中国输血杂志

【Objective】 To investigate the effect and prognosis of Roxastat combined with levocarnitine and polysaccharide iron complex in patients with chronic renal failure hemodialysis anemia(CRFHA). 【Methods】 A total of 70 patients with CRFHA treated in our hospital from January 2019 to December 2020 were selected as study subjects. They were divided into control group and treatment group by simple randomizaiton grouping method. After 5 cases in each group dropped out due to transfer, COVID-19 epidemic and missed follow-up, 30 cases were left in each group.The control group was treated with Roxastat, and the treatment group with L-carnitine and polysaccharide iron complex based on Roxastat. The differences in anemia parameters, iron metabolism, dialysis-related indexes and complications between the two groups were observed and compared. 【Results】 After 3 months of treatment, Hb, RBC, Hct, TIBC, FE, and FERR in the treatment group were significantly higher than those in the control group (118.36±6.64 vs 109.34±6.25, 4.32±0.264 vs 4.03±0.32, 32.37±3.30 vs 29.85±3.24, 67.62±10.66 vs 62.78±10.32, 17.87±3.81 vs 12.51±3.82, 389.37±18.30 vs 362.85±18.04, respectively, P0.05). Blood creatinine of patients after 3 months of treatment was significantly higher (control group: 1 016.27±122.14 vs 1 052.27±96.23; observation group 1 014.23±121.57 vs 1 056.25±96.82, P<0.05); blood phosphorus (control group: 2.21±0.21vs 2.14±0.21; observation group: 2.23±0.30 vs 2.15±0.64) was significantly lower(P<0.05); blood calcium (control group: 2.07±0.51 vs 1.85±0.54; observation group 2.05±0.50 vs 1.87±0.52) was significantly lower (P<0.05 ). A comparison of complications between the two groups of patients after 6 months of treatment showed that the combined incidence of gastrointestinal function, increased blood pressure, and fever in the treatment group was lower than that in the control group, and the difference was statistically significant (P<0.05). 【Conclusion】 Roxastat combined with L-carnitine and polysaccharide iron complex in patients with CRFHA has definite effect, which improves dialysis-related indicators, has great advantages in optimizing anemia parameters and iron metabolism, and provides reference value for clinical treatment of CRFHA

Levocarnitine for pegasparaginase-induced hepatotoxicity in acute lymphoblastic leukemia.

Pegasparaginase (PEG-Asp), commonly used in acute lymphoblastic leukemia (ALL), is associated with hyperbilirubinemia and elevated transaminases. Treatment of acute hepatotoxicity is limited to case studies reporting success with levocarnitine (LC). In a retrospective analysis, 25 ALL patients experienced Grade ≥3 hyperbilirubinemia and/or elevated transaminases following a single dose of PEG-Asp where 12 patients received LC compared to 13 patients with no intervention. Median LC dose was 50 mg/kg/day for a median of 11 days. Median values were greater in the LC group: total bilirubin 5.2 mg/dL vs 4.5 mg/dL (p = 0.19), AST 75.5 units/L vs. 30 units/L (p = 0.05), and ALT 263.5 units/L vs 47 units/L (p = 0.003). Time to resolution (TTR) did not significantly differ between LC and control (p = 0.08), however, patients on LC did resume therapy sooner (p = 0.17). Although significant limitations exist in the study, LC did not result in a clinically significant impact when used to treat PEG-Asp-induced hepatotoxicity.

Valproic acid rechallenge after valproate-induced hyperammonemic encephalopathy.

A 24-year-old man with a past medical history of behavioral disturbances and spastic tetraplegia secondary to traumatic brain injury presented to the psychiatry consult service with acute exacerbation of agitation and aggression. The patient's behavioral disturbances were previously reduced with 1500 mg daily of valproic acid (VPA). Prior to admission, VPA was discontinued due to elevated serum ammonia levels of 96 µmol/L and clinical findings consistent with valproate-induced hyperammonemic encephalopathy (VIHE), such as lethargy, confusion, frank delirium, and ataxia. Current guidelines for treating VIHE suggest either a complete discontinuation of the drug or a drug rechallenge with the addition of levocarnitine or carglumic acid supplementation. In this case, VPA was rechallenged without supplementation to decrease the risk of noncompliance. The patient received a lower dose of VPA with subsequent up-titration. His ammonia level decreased to an acceptable level. This case report discusses the challenges of managing VIHE in patients requiring VPA and discusses opportunities for further research in preventing VIHE.

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia.

Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.