Acetyl-L-Carnitine (ALCAR)

BACKGROUND: Ageing is characterized by a gradual decline in body function, representing the clinical situation called "frailty". Prefrailty is the intermediate stage between frailty and robust condition. L-carnitine (LC) plays an important role in energy production from long-chain fatty acids in mitochondria, and its serum level is lower in prefrail and frail subjects. OBJECTIVE: This study aims to evaluate the effect of Acetyl-L-carnitine (ALCAR) in pre-frail older patients. METHODS: We scheduled 3 months of treatment and then 3 months of follow-up. A total of 92 subjects were selected from May, 2009 to July, 2017, in a randomized, observational, double-blind, placebo-controlled study. We scheduled 3 months of treatment and then 3 months of follow-up. ALCAR (oral 1.5 g/bis in die - BID) or placebo groups were used. RESULTS: After the treatment, only the treated group displayed a decrease in C reactive protein (CRP) p < 0.001 and an increase in serum-free carnitine and acetylcarnitine (p < 0.05) in Mini-Mental state (MMSE) p < 0.0001 and 6-walking distance (p < 0.0001); ALCAR group vs. placebo group showed a decrease in HDL cholesterol and CRP (p < 0.01), an increase in MMSE score (p < 0.001) and in the 6-walking distance (p < 0.001). CONCLUSIONS: ALCAR treatment delays the incidence and severity of onset of degenerative disorders of the elderly in prefrail subjects with improvement in memory and cognitive processes.

Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium-permeable N-methyl-d-aspartic acid receptors. Adverse drug-drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug-drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24 h post-fertilization (hpf), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl l-carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65, a zebrafish ortholog of human CYP3A4, both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells.

Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1-0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. Published by Elsevier Inc.

Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

The cellular events involved in acetyl-L-carnitine (ALCAR) analgesia were investigated in the mouse hot plate test. I.c.v. pretreatment with aODNs against the alpha subunit of G(q) and G(11) proteins prevented the analgesia induced by ALCAR (100 mg kg(-1) s.c. twice daily for 7 days). Administration of the phospholipase C (PLC) inhibitors U-73122 and neomycin, as well as the injection of an aODN complementary to the sequence of PLCbeta(1), antagonized the increase of the pain threshold induced by ALCAR. Pretreatment with U-73343, an analogue of U-73112 inactive on PLC, did not modify ALCAR analgesic effect. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or pretreatment with TMB-8, a blocker of Ca(++) release from intracellular stores, the antinociception induced by ALCAR was dose-dependently antagonized. I.c.v. treatment with heparin, an IP(3) receptor antagonist, prevented the increase of pain threshold induced by the investigated compound, analgesia that was restored by co-administration of D-myo-inositol. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitors calphostin C and cheleritryne, resulted in a dose-dependent potentiation of ALCAR antinociception. The administration of PKC activators, such as PMA and PDBu, dose-dependently prevented the ALCAR-induced increase of pain threshold. Neither aODNs nor pharmacological treatments produced any behavioral impairment of mice as revealed by the rota-rod and hole board tests. These results indicate that central ALCAR analgesia in mice requires the activation of the PLC-IP(3) pathway. By contrast, the simultaneous activation of PKC may represent a pathway of negative modulation of ALCAR antinociception.

Abstract Acute cocaine administration increases phosphorylation of dopamine and cAMP-regulated phosphoprotein (M(r) 32 kDa) (DARPP-32) at threonine (Thr)-34, whereas repeated cocaine administration increases DARPP-32 phosphorylation at Thr-75 in Sprague-Dawley rat striatum. Repeated acetyl-l-carnitine (ALCAR) administration persistently increases dopamine outflow in the nucleus accumbens. The present study examined the effect of repeated ALCAR administration on the DARPP-32 phosphorylation pattern in the nucleus accumbens and caudate-putamen. ALCAR increased phosphoThr-34 DARPP-32 levels and decreased phosphoThr-75 DARPP-32 levels, after 1 and 10 days of washout. We compared the effects of repeated cocaine and repeated ALCAR administrations on the behavioural response to cocaine challenge and on the DARPP-32 phosphorylation pattern and cyclin-dependent kinase 5 (Cdk5) levels in the striatum. We also studied whether ALCAR administered daily during or after cocaine sensitization procedure would interfere with the effects of cocaine. When the response to the cocaine challenge was assessed, cocaine- and ALCAR-treated rats showed a similar sensitized behavioural response, and rats receiving combined cocaine and ALCAR treatments, irrespective of treatment order, also showed a sensitized response. A week after the cocaine challenge, the two drugs had induced opposite modifications in DARPP-32 phosphorylation, as cocaine increased phosphorylation at Thr-75, while ALCAR increased phosphorylation at Thr-34. In cocaine plus ALCAR treated rats, irrespective of treatment order, ALCAR administration antagonized cocaine effects on DARPP-32 phosphorylation. Moreover, cocaine, but not ALCAR, increased DeltaFosB and Cdk5 expression, and the increase in Cdk5 was antagonized by ALCAR administration in rats receiving combined treatments. These effects were relatively persistent, as they were still present 7 days after the last treatment.

Acetyl-L-carnitine (ALCAR) plays an integral role in the transport of long chain fatty acids across the inner mitochondrial membrane for oxidative phosphorylation. In non-human primates, administration of ALCAR was reported to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurological injury to the substantia nigra. The present study investigates the effects of ALCAR against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), the neurotoxic metabolite of MPTP, in murine brain neuroblastoma cells. MPP(+), a potent mitochondrial toxin, induced a dose-dependent reduction in mitochondrial oxygen consumption and cell viability, corresponding to an accelerated rate of cellular glucose utilization. Treatment with ALCAR, but not L-carnitine, prevented MPP(+) toxicity and partially restored intracellular ATP concentrations, but did not reverse the MPP(+)-induced loss of mitochondrial oxygen consumption. These data indicate that protective effects are independent of oxidative phosphorylation. ALCAR had a substantial glucose sparing effect in both controls and MPP(+)-treated groups, demonstrating a potential role in enhancing glucose utilization through glycolysis. Antagonizing the entry of fatty acids into the mitochondria, with either insulin or malonyl CoA, did not interfere with ALCAR protection against MPP(+). On the contrary, insulin potentiated the protective effects of ALCAR. In conclusion, these data indicate that ALCAR protects against MPP(+) toxicity, independent of mitochondrial oxidative capacity or beta-oxidation of fatty acids. In contrast, the protective effects of ALCAR appear to involve potentiation of energy derived from glucose through anaerobic glycolysis.

BACKGROUND: Fatigue is reported to occur in up to 92% of patients with multiple sclerosis (MS) and has been described as the most debilitating of all MS symptoms by 28% to 40% of MS patients. OBJECTIVES: To assess whether carnitine (enteral or intravenous) supplementation can improve the quality of life and reduce the symptoms of fatigue in patients with MS-related fatigue and to identify any adverse effects of carnitine when used for this purpose. SEARCH STRATEGY: A literature search was performed using Cochrane MS Group Trials Register (21 May 2009), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2009, issue 2, MEDLINE (PubMed) (1966-21 May 2009), EMBASE (1974-21 May 2009). Reference lists of review articles and primary studies were also screened. A hand search of the abstract book of recent relevant conference symposia was also conducted. Personal contact with MS experts and a manufacturer (Source Naturals, United States) of carnitine formulation was contacted to determine if they knew of other clinical trials. No language restrictions were applied. SELECTION CRITERIA: Full reports of published and unpublished randomized controlled trials and quasi-randomized trials of any carnitine intervention in adults with a clinical diagnosis of fatigue associated with multiple sclerosis were included. DATA COLLECTION AND ANALYSIS: Data from the eligible trials was extracted and coded using a standardized data extraction form and entered into RevMan 5. Discrepancies were to be resolved by discussion with a third reviewer however this was not necessary. The quality items to be assessed were method of randomization, allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention-to-treat analysis and completeness of follow up. MAIN RESULTS: The search identified one randomized cross-over trial. In this study patients were exposed to both acetyl L-carnitine (ALCAR(tm)) 2 grams daily and amantadine 200 mg daily in adult patients with relapsing-remitting and secondary progressive MS. The effects of carnitine on fatigue are not clear based on the one included crossover RCT. There was no difference b

The food supplement acetylcarnitine is marketed for use in neurological support; however, research on its bioavailability and metabolic fate has been limited. This study investigated the absorption, metabolism, and excretion of acetylcarnitine compared with those of carnitine. Healthy volunteers received either carnitine or an acetylcarnitine supplement (0.5 or 1.5 g). Plasma and urine samples were collected at baseline and at multiple time points (1-48 h) post intake and analyzed using LC‒MS/MS. Both carnitine and acetylcarnitine exhibited low intestinal absorption and renal reabsorption. The peak plasma concentrations increased over the baseline values by 48% (acetylcarnitine) and 43% (carnitine) following a 1.5 g dose. However, the increase in area under the curve (ΔAUC) from acetylcarnitine was 7.7-fold lower than that from carnitine. Elevated plasma levels of carnitine and acetylcarnitine led to a 5-fold increase in clearance, and a substantial portion of the supplements were excreted via urine. The acetylcarnitine supplement was mostly eliminated in the form of carnitine. Approximately 90% of both supplements were metabolized to TMAO, reaching 50 µM in plasma-levels previously found to be associated with adverse health outcomes. Acetylcarnitine has significantly lower bioavailability than carnitine. The intake of both supplements resulted in substantial TMAO production, raising potential health concerns. © 2025 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.

Polycystic ovary syndrome is a complex heterogenous reproductive endocrine disorder affecting mainly reproductive age women worldwide. The syndrome primarily is associated with hyperandrogenism, hyperinsulinemia, menstrual irregularity, infertility, hormonal dysregulation and obesity. Here, we examined the effects of Acetyl-L-Carnitine, L-Arginine, CoQ10, (Carnitine + Arginine + CoQ10) and Metformin, alone and in combination, on PCOS management. The trial included 63 females diagnosed with PCOS. The participants were treated with either Carnitine + Arginine + CoQ10 alone (nutraceutical group) or in combination with metformin (combination group) for six months. The outcome measures included demographic, anthropometric, clinical, endocrine, metabolic, quality of Life and stress response of the participants. Over 24 weeks, both treatment regimens improved metabolic, hormonal, and psychological outcomes in women with PCOS. Repeated-measures ANCOVA showed significant group × time interactions for BMI (p < .001, η2 = .220), waist circumference (p < .001, η2 = .314), and hip circumference (p < .001, η2 = .428), favoring the combination group. Hormonal responses varied: DHEAS (p = .045, η2 = .082), FAI (p < .001, η2 = .223), testosterone (p = .004, η2 = .113), and prolactin (p = .032, η2 = .072) declined more in the combination group, whereas LH decreased more in the nutraceutical group (p < .001, η2 = .231). Quality of life improved significantly in both arms, with greater gains in the combination group (p = .037, η2 = .071). Oxidative stress (MDA) also declined significantly in both groups (p = .003), with larger numerical reductions in the combination arm (- 22% vs - 6%), though between-group differences were not significant (p = .329). Both nutraceutical and combination therapies led to significant improvements in metabolic, hormonal, and psychological outcomes in women with PCOS over 24 weeks. Repeated-measures ANCOVA confirmed greater reductions in BMI, waist and hip circumference, DHEAS, FAI, testosterone, and prolactin, as well as superior quality-of-life gains with combination therapy. Nutraceutical therapy exerted stronger effects on LH suppression, while oxid

STUDY QUESTION: Does the addition of three antioxidants to culture media during gamete collection, insemination, and embryo culture increase the clinical pregnancy rate from fresh blastocyst transfers? SUMMARY ANSWER: The clinical pregnancy rate from fresh blastocyst transfers was not increased by the addition of antioxidants to IVF and embryo culture media. WHAT IS KNOWN ALREADY: Addition of antioxidants to media is beneficial in mouse IVF, embryo culture, and cryopreservation. Prospective clinical trials of sibling human oocytes found an improvement in embryo quality and increased pregnancy rates from frozen blastocyst transfers in older patients. STUDY DESIGN, SIZE, DURATION: Single-centre, prospective randomized controlled trial, superiority study comparing media with or without the addition of antioxidants from January 2019 to November 2021. A total of 1482 patients were randomized before egg collection. Patients and their doctors were blinded to the treatment group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing IVF/ICSI cycles and intending to undergo a fresh transfer of a single blastocyst were recruited. Exclusion criteria were previous participation in the study, use of cryopreserved oocytes/embryos, artificial oocyte activation, freeze-all cycle, or extraction of sperm from testicular biopsy. Seven hundred thirty-nine patients were randomized to control media and 743 patients to media containing the 'A3' antioxidant combination of acetyl-L-carnitine, α-lipoic acid, and N-acetyl-L-cysteine (treatment group). MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate per randomized patient per cycle from fresh embryo transfer was not different between the control and antioxidant media (26.1% vs 22.9%; P > 0.05; RR 0.88 (95% CI 0.73-1.05)). In the Per Protocol population, which excludes patients with protocol violations or without a fresh transfer due to freeze-all or no embryo available, there was also no difference in between the control and antioxidant media in clinical pregnancy rate (36.7% vs 33.2%; P > 0.05; RR 0.90 (95% CI 0.76-1.07)) and live birth rate (32.4% vs 29.5%, P > 0.05). In the Intention-to-Treat population, antioxi

Background/Objectives: This study aimed to evaluate the effects of four weeks of combined Acetyl-l-Carnitine and alpha-lipoic acid (ALA) supplementation on anaerobic and aerobic performance and fatigue resistance in trained cyclists, hypothesizing improvements in maximal aerobic power (MAP), Wingate test performance, and reduced lactate accumulation. Methods: In a double-blind, randomized trial, 41 male trained cyclists (age: 36 ± 12 years; MAP: 4.35 ± 0.60 W·kg-1) were assigned to a supplement group (SUP, n = 19; 1200 mg/day Acetyl-l-Carnitine, 300 mg/day ALA, 1.1 mg Vitamin B1, 2.5 µg Vitamin B12) or placebo group (PLA, n = 22) for four weeks. Performance was assessed pre- and post-intervention via counter-movement jumps (CMJs), Wingate tests (WG1, WG2), and a graded exercise test (GXT). Blood lactate ([La-]) was measured post-Wingate. A three-way mixed ANOVA analyzed Wingate performance (session, order, and group), and a two-way ANOVA assessed MAP and fatigue effects. Results: MAP increased by 3.4% (314 ± 32 W to 324 ± 37 W; p = 0.005) with no group interaction (p = 0.457). Wingate peak power showed main effects for order (p < 0.001) and session (p = 0.011) but no group interaction (p = 0.676). SUP reduced [La-] by 1.5 mmol·L-1 post-WG2 in POST (p = 0.049). No significant group differences were found for CMJ or fatigue metrics. Conclusions: Four weeks of Acetyl-l-Carnitine and ALA supplementation did not enhance aerobic or anaerobic performance in trained cyclists, despite reducing blood lactate after high-intensity exercise, suggesting no ergogenic benefits.

Background: This systematic review aimed to evaluate the efficacy and safety of dietary supplements in breast cancer patients, focusing on their impact on clinical outcomes, treatment-related side effects, and therapy adherence. Methods: Only RCTs investigating the effects of various orally administered supplements in adult breast cancer patients were included. Well-defined substances like vitamins, minerals, antioxidants, and specific herbal extracts were explored. The review excluded studies solely based on dietary interventions or non-supplemental approaches. The primary outcome assessed was quality of life. Secondary outcomes included disease-free survival, overall survival, tumor response, and biomarkers indicative of disease progression. Results: A total of 45 randomized controlled trials (RCTs) were included in this systematic review. Overall, supplementation was not associated with serious adverse events in the included trials. Vitamin D supplementation showed promise in some studies, with potential immunomodulatory and antioxidant effects, particularly when combined with other interventions. Omega-3 fatty acids and beta-glucan demonstrated potential in alleviating certain symptoms and improving quality of life. Studies on amino acids like acetyl-L-carnitine and L-arginine also yielded mixed results. Beta-glucan exhibited potential for immune-enhancing effects, while melatonin and creatine showed limited or no benefit for fatigue or muscle strength. Herbal extracts, including silymarin, curcumin, and EGCG, had varied effects. Curcumin studies presented mixed results. Silymarin showed potential for hepatoprotective effects. Conclusions: These findings highlight the potential of specific dietary supplements to improve various aspects of breast cancer care. However, the evidence is mixed across supplement types, and further research is needed to determine the most effective and safe approaches.

Patients with long-chain fatty acid oxidation disorders (LC-FAOD) have impaired endogenous ketone production due to defects in the beta-oxidation pathway. We explored supplementation of exogenous D-beta-hydroxybutyrate (D-BHB) as an alternative source of energy in a randomized, double-blinded crossover pilot study. Participants ≥18 years of age with a diagnosis of LC-FAOD completed two moderate-intensity treadmill exercises following an oral supplementation of D-BHB salts or an isocaloric maltodextrin beverage. Five subjects (1 VLCADD, 2 CPT2D, 2 LCHADD), 60 % male, mean age = 33 years were enrolled. Mild to moderate GI symptoms were related to ingestion of D-BHB. Plasma D-BHB was increased after oral D-BHB compared to maltodextrin (p < .001) with an average concentration of 0.43 mM in the post-exercise period. During exercise, free fatty acids (p = .01), fold change in long-chain acylcarnitine species (LC-AC) (p ≤ .03) and systolic BP (p = .02) were lower after D-BHB compared to the maltodextrin beverage. D-BHB suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitines. There were no differences between beverages in acetylcarnitine, blood glucose, creatine kinase, VO2, HR, RPE or respiratory exchange ratio. Consumption of the D-BHB beverage was safe and well-tolerated. Plasma D-BHB levels achieved mild ketosis and suppressed lipolysis and the associated rise in LC-AC, but fell short of stimulating the energetic effects that might have resulted in altered exercise parameters such as RER, or HR. In conclusion, our results provide a strong rationale for future studies aimed toward defining the optimal multiple-dose regimen of D-BHB per day that might improve exercise tolerance and understanding the long-term impact of treatment in LC-FAOD subjects.

The literature on the postprandial metabolic changes in individuals with Metabolic Syndrome (MetS) remains limited, despite the fact that postprandial states represent the most common physiological condition in Western societies. BACKGROUND/OBJECTIVES: The objective of this study was to investigate the plasma metabolomics profile in both fasting and postprandial states following a high-fat challenge in individuals with MetS who consumed diets with varying quantities and qualities of dietary fat over 12 weeks. METHODS: Seventy-five patients with MetS (28 males and 47 females) from the Spanish LIPGENE cohort were included in the study. MetS patients were randomly stratified to follow one of four dietary interventions (isoenergetic diets) for a 12-week long-term study. The four diets were high in saturated fatty acids and high in monounsaturated fatty acids (HSFA and HMUFA), low-fat high-complex carbohydrates (LFHCC), and LFHCC supplemented with n-3. The metabolomics analysis of plasma samples was carried out using Liquid Chromatography Time-of-Flight Mass Spectrometry (LC-TOF/MS). RESULTS: We observed a decrease in inflammation biomarkers, including acetylcarnitine and L-carnitine during the fasting state and hexanoyl-L-carnitine and isobutyryl-L-carnitine during the postprandial period, mediated by the replacement of HSFA with HMUFA. Additionally, antioxidant compounds such as 4-hydroxybenzaldehyde and L-valine were expressed at higher levels after consumption of the HMUFA diet compared to the HSFA diet. HSFA also presented altered levels of phosphatidylcholine, a metabolite previously linked with insulin resistance. CONCLUSIONS: These findings suggest that replacing HSFA with HMUFA may reduce inflammation and improve antioxidant profiles, supporting the potential for tailored dietary interventions in individuals with MetS.

BACKGROUND: Although nutraceutical-based treatments are often offered for erectile dysfunction (ED), their efficacy remains doubtful, and the choice of one substance over the other is challenged by the dearth of head-to-head comparative studies. AIM: We aimed to compare the efficacy of available nutraceutical interventions, alone or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in improving erectile function in men with ED through a network meta-analysis (NMA), which incorporates direct and indirect evidence into one model thus generating a hierarchy of effectiveness. METHODS: PubMed, Scopus, Web of Sciences, and Cochrane Library databases were searched for randomized placebo-controlled trials (RCTs) assessing the effect of any nutraceutical regimen in improving erectile function when compared to each other, placebo, and/or PDE5i in men with ED. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Two NMAs were also conducted separately for organic and non-organic ED. Reciprocal comparisons between all treatments were analyzed by league tables. OUTCOMES: The main outcome was the standardized mean difference in the score of the International Index of Erectile Function (IIEF)-5 or IIEF-6. RESULTS: Fifteen RCTs provided information on 1000 men with ED. In the overall NMA, compared to placebo, the combination propionyl L-carnitine (PLC) + acetyl L-carnitine (ALC) + Sildenafil was associated with the highest SUCRA (97%) in improving erectile function score, followed by L-Arginine + Tadalafil (84%), Sildenafil (79%), Tadalafil (72%), and L-Arginine (52%). No other treatment regimen showed efficacy with statistical significance. In patients with organic ED, the efficacy of Sildenafil and Tadalafil was significantly improved by PLC + ALC and L-Arginine, respectively. On the contrary, in non-organic ED, nutraceuticals did not improve the therapeutic performance of daily Tadalafil. CLINICAL IMPLICATIONS: This NMA contributes valuable insights into the potential of nutraceutical interventions for ED. STRENGTHS AND LIMITATIONS: We employed strict inclusion criteria relat

Oxidative stress is one of the main mechanisms responsible for male infertility. Various conditions such as varicocele, obesity, advanced age, and lifestyle can lead to an increase in reactive oxygen species, causing an oxidative imbalance in the reproductive environment. Spermatozoa are sensitive to reactive oxygen species and require energy to carry out their main function of fertilizing the egg. Excessive reactive oxygen species can affect sperm metabolism, leading to immobility, impaired acrosome reaction, and cell death, thereby impairing reproductive success. This double-blind randomized study evaluated the effect of supplementation with L-carnitine, acetyl-L-carnitine, vitamins, and other nutrients on semen quality in 104 infertile patients with or without varicocele, while also investigating the impact of factors such as obesity and advanced age on treatment. Sperm concentration significantly increased in the supplemented group compared to the placebo group ( P = 0.0186). Total sperm count also significantly increased in the supplemented group ( P = 0.0117), as did sperm motility ( P = 0.0120). The treatment had a positive effect on patients up to 35 years of age in terms of sperm concentration ( P = 0.0352), while a body mass index (BMI) above 25 kg m -2 had a negative effect on sperm concentration ( P = 0.0110). Results were not showing a net benefit in stratifying patients in accordance with their BMI since sperm quality increase was not affected by this parameter. In conclusion, antioxidant supplementation may be beneficial for infertile patients and has a more positive effect on younger patients with a normal weight.

Background and Objectives: In the Western world, back pain and sciatica are among the main causes of disability and absence from work with significant personal, social, and economic costs. This prospective observational study aims to evaluate the effectiveness of a rehabilitation program combined with the administration of Alpha Lipoic Acid, Acetyl-L-Carnitine, Resveratrol, and Cholecalciferol in the treatment of sciatica due to herniated discs in young patients in terms of pain resolution, postural alterations, taking painkillers, and quality of life. Materials and Methods: A prospective observational study was conducted on 128 patients with sciatica. We divided the sample into 3 groups: the Combo group, which received a combination of rehabilitation protocol and daily therapy with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol for 30 days; the Reha group, which received only a rehabilitation protocol; and the Supplement group, which received only oral supplementation with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol. Clinical assessments were made at the time of recruitment (T0), 30 days after the start of treatment (T1), and 60 days after the end of treatment (T2). The rating scales were as follows: the Numeric Rating Scale (NRS); the Oswestry Disability Questionnaire (ODQ); and the 36-item Short Form Health Survey (SF-36). All patients also underwent an instrumental stabilometric evaluation. Results: At T1, the Combo group showed statistically superior results compared to the other groups for pain (p < 0.05), disability (p < 0.05), and quality of life (p < 0.05). At T2, the Combo group showed statistically superior results compared to the other groups only for pain (p < 0.05) and quality of life (p < 0.05). From the analysis of the stabilometric evaluation data, we only observed a statistically significant improvement at T2 in the Combo group for the average X (p < 0.05) compared to the other groups. Conclusions: The combined treatment of rehabilitation and supplements with anti-inflammatory, pain-relieving, and antioxidant action is effective in the t

OBJECTIVES: Fibromyalgia (FM) is characterised by a form of debilitating pain that is unresponsive to standard analgesics. The aim of this study was to evaluate the efficacy of supplementing ongoing pregabalin (PGB) and duloxetine (DLX) treatment with palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) for 24 weeks in FM patients. METHODS: After undergoing three months of stable treatment with DLX+PGB, FM patients were randomised to continue the same treatment (Group 1) or to add PEA 600 mg b.i.d + ALC 500 mg b.i.d. (Group 2) for a further 12 weeks. Every two weeks throughout the study, cumulative disease severity was estimated using the Widespread Pain Index (WPI) as the primary outcome measure; the secondary outcomes were the fortnightly scores of the patient-completed revised Fibromyalgia Impact Questionnaire (FIQR) and the modified Fibromyalgia Assessment Status (FASmod) questionnaire. All three measures were expressed as time-integrated area under the curve (AUC) values. RESULTS: One hundred and thirty (91.5%) of the initial 142 FM patients completed the study: 68 patients in Group 1 and 62 in Group 2. Twenty-four weeks after randomisation, the Group 2 patients showed additional significant improvements in all three outcome measures. Although there was some fluctuation in both groups during the study period, the AUC values of the WPI scores steadily decreased in Group 2 (p=0.048), which also showed better outcomes in terms of the AUC values of the FIQR (p=0.033) and FASmod scores (p=0.017). CONCLUSIONS: This is the first randomised controlled study demonstrating the effectiveness of the adding on therapy of PEA+ALC to DLX+PGB in FM patients.

Hyperlipidemia is a key risk factor for cardiovascular disease, and it is associated with lipid metabolic disorders and gut microbiota dysbiosis. Here, we aimed to investigate the beneficial effects of 3-month intake of a mixed probiotic formulation in hyperlipidemic patients (n = 27 and 29 in placebo and probiotic groups, respectively). The blood lipid indexes, lipid metabolome, and fecal microbiome before and after the intervention were monitored. Our results showed that probiotic intervention could significantly decrease the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (P < 0.05), while increasing the levels of high-density lipoprotein cholesterol (P < 0.05) in patients with hyperlipidemia. Probiotic recipients showing improved blood lipid profile also exhibited significant differences in their lifestyle habits after the 3-month intervention, with an increase in daily intake of vegetable and dairy products, as well as weekly exercise time (P < 0.05). Moreover, two blood lipid metabolites (namely, acetyl-carnitine and free carnitine) significantly increased after probiotic supplementation cholesterol (P < 0.05). In addition, probiotic-driven mitigation of hyperlipidemic symptoms were accompanied by increases in beneficial bacteria like Bifidobacterium animalis subsp. lactis and Lactiplantibacillus plantarum in patients' fecal microbiota. These results supported that mixed probiotic application could regulate host gut microbiota balance, lipid metabolism, and lifestyle habits, through which hyperlipidemic symptoms could be alleviated. The findings of this study urge further research and development of probiotics into nutraceuticals for managing hyperlipidemia. IMPORTANCE The human gut microbiota have a potential effect on the lipid metabolism and are closely related to the disease hyperlipidemia. Our trial has demonstrated that 3-month intake of a mixed probiotic formulation alleviates hyperlipidemic symptoms, possibly by modulation of gut microbes and host lipid metabolism. The findings of the present study provide new insights into the treatment of hyperlipidemia, mechanisms of novel therapeutic strategies, and appl

BACKGROUND: In pregnancy, choline is deemed an essential nutrient and carnitine needs are increased, but amounts remain undefined. OBJECTIVES: We aimed to measure choline and total dietary protein and dairy protein intake from food and supplements across pregnancy and the response to intake by profiling choline and carnitine metabolites across pregnancy and in cord blood. METHODS: An exploratory analysis of choline and protein intake from 3-d diet records and measures of 36 serum choline and carnitine metabolites in early (12-17 wk) and late (36-38 wk) pregnancy was conducted in participants from the Be Healthy in Pregnancy study randomized to high dairy protein+walking exercise or usual care. Metabolites were measured in fasted maternal and cord serum using multisegment injection-capillary electrophoresis-mass spectrometry. Mixed ANOVA adjusted for body mass index was performed for comparison of metabolites across pregnancy and between intervention and control. RESULTS: In 104 participants, the median (Q1, Q3) total choline intake was 347 (263, 427) mg/d in early and 322 (270, 437) mg/d in late pregnancy. Only ∼20% of participants achieved the recommended adequate intake (450 mg/d) and ∼10% consumed supplemental choline (8-200 mg/d). Serum-free choline (μmol/L) was higher in late compared with early pregnancy [12.9 (11.4, 15.1) compared with 9.68 (8.25, 10.61), P < 0.001], but choline downstream metabolites were similar across pregnancy. Serum carnitine [10.3 (9.01, 12.2) compared with 15.9 (14.1, 17.9) μmol/L, P < 0.001] and acetylcarnitine [2.35 (1.92, 2.68) compared with 3.0 (2.56, 3.59), P < 0.001] were significantly lower in late pregnancy. High cord:maternal serum metabolite ratios were found in most measured metabolites. CONCLUSIONS: Despite inadequate choline intake, serum-free choline was elevated in late pregnancy and enriched in cord blood compared with maternal serum. Serum carnitine declined in late pregnancy despite a high protein diet. The higher cord:maternal concentrations in choline and carnitine metabolites suggest active uptake in late pregnancy, reflecting the importance of these circulating metabolites in fetal development. This trial was

This narrative review was conducted using searches of the PubMed/Medline and Google Scholar databases from inception to November 2019. Clinical trials and relevant articles were identified by cross-referencing major depressive disorder (and/or variants) with the following terms: folate, homocysteine, S-adenosylmethionine (SAMe), L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, L-tryptophan, zinc, magnesium, vitamin D, omega-3 fatty acids, coenzyme Q10, and inositol. Manual reviews of references were also performed using article reference lists. Abnormal levels of folate, homocysteine, and SAMe have been shown to be associated with a higher risk of depression. Numerous studies have demonstrated antidepressant activity with L-methylfolate and SAMe supplementation in individuals with depression. Additionally, the amino acids L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, and L-tryptophan have been implicated in the development of depression and shown to exert antidepressant effects. Other agents with evidence for improving depressive symptoms include zinc, magnesium, omega-3 fatty acids, and coenzyme Q10. Potential biases and differences in study designs within and amongst the studies and reviews selected may confound results. Augmentation of antidepressant medications with various supplements targeting nutritional and physiological factors can potentiate antidepressant effects. Medical foods, particularly L-methylfolate, and other supplements may play a role in managing depression in patients with inadequate response to antidepressant therapies.

AIM: To investigate the efficacy of Superoxide Dismutase, Alpha Lipoic Acid, Acetyl L-Carnitine, and Vitamin B12 (B12) in one tablet in Diabetic Neuropathy (DN). PATIENTS-METHODS: In this prospective, double-blind, placebo-controlled study, 85 patients with Diabetes Mellitus Type 2 (DMT2) were randomly assigned, either to receive the combination of four elements (active group, n = 43), or placebo (n = 42) for 12 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured the vibration perception threshold (BIO), and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Pain (PS) and quality of life (QL) questionnaires were administered. RESULTS: At follow-up, BIO, MNSIQ, QL, PAIN, and SNCV, SNAP, and B12 levels had significantly improved inactive group (p <0.001, p <0.001, p <0.001, p <0.001, p = 0.027, p = 0.031, and p <0.001 respectively), whereas the inplacebo group MCR (mean circular resultant) and PAIN deteriorated (p <0.001, p <0.001). The changes in MNSIQ, QL, SNCV, BIO, and PAIN differed significantly between groups (p <0.001, p <0.001, p = 0.031, p <0.001, and p <0.001 respectively). CONCLUSIONS: The combination of the four elements in one tablet for 12 months in patients with DMT2 improved all indices of peripheral neuropathy, including SNAP and SNCV, pain, and Quality of Life perception, except CARTs and MNSIE.