Palmitoylethanolamide and acetyl-L-carnitine act synergistically with duloxetine and pregabalin in fibromyalgia: results of a randomised controlled study.

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.

Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for ß-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials. OBJECTIVES: To assess the effects of ALC for the treatment of DPN. SEARCH METHODS: On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer. AUTHORS' CONCLUSIONS: We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.

Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis.

OBJECTIVE: Deficiency of acetyl-L-carnitine (ALC) seems to play a role in the risk of developing depression, indicating a dysregulation of fatty acid transport across the inner membrane of mitochondria. However, data about ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs). METHODS: A literature search in major databases, without language restriction, was undertaken from inception until 30 December 2016. Eligible studies were RCTs of ALC alone or in combination with antidepressant medications, with a control group taking placebo/no intervention or antidepressants. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were used for summarizing outcomes with a random-effect model. RESULTS: Twelve RCTs (11 of which were ALC monotherapy) with a total of 791 participants (mean age = 54 years, % female = 65%) were included. Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms (SMD = -1.10, 95% CI = -1.65 to -0.56, I = 86%). In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants in reducing depressive symptoms (SMD = 0.06, 95% CI = -0.22 to 0.34, I = 31%). In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group than in the antidepressant group. Subgroup analyses suggested that ALC was most efficacious in older adults. CONCLUSIONS: ALC supplementation significantly decreases depressive symptoms compared with placebo/no intervention, while offering a comparable effect with that of established antidepressant agents with fewer adverse effects. Future large scale trials are required to confirm/refute these findings.

Mania associated with self-prescribed acetyl-l-carnitine in a man with bipolar I disorder.

OBJECTIVE: Complementary medicines are readily available and becoming increasingly popular. Acetyl-l-carnitine (ALC) is widely recognised as a safe dietary supplement to aid weight loss. We present the case of a patient who had a relapse of mania in the context of ALC use for weight loss over a two week period, on the background of bipolar I disorder previously in remission. The patient's symptoms resolved a few days after ALC was ceased. CONCLUSIONS: Given the high rates of obesity among people with mental illness, it is possible ALC may be utilised in the hope of aiding weight loss. This case highlights the importance of psychiatrists maintaining open communication with their patients about use of complementary medicines, and the risks and benefits of their use.

A randomised controlled trial comparing duloxetine and acetyl L-carnitine in fibromyalgic patients: preliminary data.

OBJECTIVES: Fibromyalgia syndrome (FMS) is a chronic disorder characterised by widespread musculoskeletal pain, troubled sleep, disturbed mood, and fatigue. Recently published reviews have demonstrated that it is influenced by various psychological aspects, and antidepressants are now considered the treatment of choice for most patients. The aim of this randomised controlled trial was to compare the effects of duloxetine and acetyl L-carnitine on pain, depression, anxiety and well-being in FMS patients. METHODS: Sixty-five female outpatients with FMS diagnosed by a rheumatologist were recruited between January 2011 and May 2012, and randomised to receive duloxetine 60 mg/day or acetyl L-carnitine 1500 mg/day (500 mg t.i.d.). Drug efficacy and side effects were assessed by the same psychiatrist at baseline, and four and 12 weeks later. RESULTS: Both drugs led to a general clinical improvement, with positive effects on pain and depressive symptoms; but neither induced a significant improvement in anxiety. Both drugs had a positive effect on the physical component of the quality of life, but only duloxetine improved the psychological component. CONCLUSIONS: Although they need to be confirmed by further studies, these preliminary findings confirm the efficacy of duloxetine, and suggest that acetyl L-carnitine is also efficacious in improving depressive symptoms, pain, and the quality of life of FMS patients.

Pharmacological interventions for cognitive decline in people with Down syndrome.

BACKGROUND: People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear. OBJECTIVES: To assess the effectiveness of anti-dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome. SEARCH METHODS: In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessary. MAIN RESULTS: Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl-L-carnitine.Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow-up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias.Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) -0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI -0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death.For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI -0.43 to 0.52), behaviour (SMD -0.17, 95% CI -0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death.Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetyl-L-carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures. AUTHORS' CONCLUSIONS: Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome.

Pharmacokinetic comparisons of two acetyl-L-carnitine formulations in healthy Korean volunteers.

BACKGROUND: Acetyl-L-carnitine (ALC) has demonstrated neuroprotective effects in several experiments and is widely prescribed to reduce cognitive impairment in Alzheimer's disease patients or manage neuropathic symptoms in diabetic patients. OBJECTIVES: This study was designed to assess the pharmacokinetic (PK) bioequivalence between a new generic (test) formulation of ALC hydrochloride 590 mg and a branded (reference) formulation of ALC hydrochloride 590 mg in healthy Korean male volunteers. METHODS: This was a randomizedsequence, single-dose, two-way crossover study. All subjects randomly received one formulation of the test or reference tablet and the other formulation with a 7-day washout period. Blood samples (7 mL) were collected immediately before dosing, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 hours postdose. The plasma concentrations of ALC were analyzed using liquid chromatography tandem mass spectrometry. Tolerability was assessed throughout the study. RESULTS: The PK profiles of both formulations showed similar rends. The mean (±SD) baseline (predose) concentration of ALC was 1.23±0.31 µg/mL and 1.09±0.30 µg/mL for the test and the reference formulations, respectively. The mean Cmax for the test and reference formulations were 1.74±0.43 µg/mL and 1.68±0.48 µg/mL, respectively. The mean AUClast of ALC was 12.96±1.89 µg×h/mL and 12.49±2.44 µg×h/mL for the test and reference formulations, respectively. The geometric mean ratios of test/reference (90% CI) were 1.050 (0.960-1.149) for Cmax and 1.048 (1.000-1.099) for AUClast. Both formulations were well tolerated in all treatment groups. CONCLUSION: The test and the reference formulations of ALC were bioequivalent with regard to the PK parameters.

A double-blind, randomized phase II study to evaluate the safety and efficacy of acetyl-L-carnitine in the prevention of sagopilone-induced peripheral neuropathy.

Peripheral neuropathy (PN) is a recognized side effect of microtubule-targeting agents and the most clinically relevant toxicity observed with the epothilone sagopilone (SAG). Studies suggest that acetyl-L-carnitine (ALC) may prevent chemotherapy-induced PN. We conducted a prospective, placebo (PBO)-controlled, double-blind, randomized trial to investigate the safety and efficacy of ALC for the prevention of SAG-induced PN. Methods. Patients with ovarian cancer (OC) or castration-resistant prostate cancer (CRPC) and no evidence of neuropathy received SAG (16 mg/m(2) intravenously over 3 hours every 3 weeks) with ALC (1,000 mg every 3 days) or placebo (PBO). The primary endpoint was incidence of PN within six or fewer cycles in both treatment groups. Results. Overall, 150 patients enrolled (98 OC patients, 52 CRPC patients), with 75 per treatment arm. No significant difference in overall PN incidence was observed between treatment arms. The incidence of grade ≥3 PN was significantly lower in the ALC arm in OC patients. Median duration of neuropathy was similar between treatment arms. The best overall response (according to the modified Response Evaluation Criteria in Solid Tumors), response according to tumor markers, time-to-event variables, and discontinuations because of adverse events (AEs) were comparable between treatment arms. Conclusion. Administration of ALC with SAG did not result in a significant difference in overall PN incidence compared with a PBO. OC patients in the SAG/ALC arm had a significantly lower incidence of grade 3 or 4 PN compared with OC patients in the SAG/PBO arm.

Oral acetyl-L-carnitine treatment in hepatic encephalopathy: view of evidence-based medicine.

OBJECTIVE: To systematically review the effect of acetyl-L-carnitine in patients with hepatic encephalopathy. DESIGN: systematic review and meta-analysis. DATA SOURCES: The Cochrane Library, MEDLINE, EMBASE.com, Science Citation Index, Google search and the China Biological Medicine Database to June 2012. REVIEW METHODS: randomized placebo controlled trials of acetyl-L-carnitine in patients with hepatic encephalopathy assessing whether acetyl-L-carnitine is an effective therapy or not. No language restrictions were applied. Two reviewers independently extracted data and assessed quality. RESULTS: 7 methodologically sound randomized controlled trials were identified involving 660 participants with hepatic encephalopathy, totaling 249 with subclinical hepatic encephalopathy, 189 with West Haven grade 1, 162 with West Haven grade 2 and 60 with West Haven grade 3. Acetyl-L-carnitine was effective to improve serum ammonia level (weighted mean difference 25.90, 95% confidence intervals 20.89 to 30.91, P < 0.05) and the number connection test completion time (weighted mean difference 16.62, 95% confidence intervals 9.88 to 23.36, P < 0.05). The outcome was consistent in subgroup analyses. No publication bias was detected. Adverse events were reported infrequently and were minor. CONCLUSIONS: Acetyl-L-carnitine is promising as an effective and tolerable treatment for hepatic encephalopathy that associated with improved serum ammonia levels and the number connection test.

Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.

BACKGROUND: Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission. METHODS: This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances. RESULTS: Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures. CONCLUSION: Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.

Acetyl-L-Carnitine Exerts Neuroprotective and Anticonvulsant Effect in Kainate Murine Model of Temporal Lobe Epilepsy.

The most well-known type of focal epilepsy that is resistant to existing treatments is temporal lobe epilepsy (TLE), with seizure foci in various structures including temporal lobe, hippocampus, amygdala, entorhinal cortex, and subcortex. The most significant processes involved in the pathophysiology of temporal lobe epilepsy (TLE) are oxidative stress, inflammation, and pyroptosis. There are evidences indicating that acetyl-l-carnitine (ALC) has anti-oxidative, anti-inflammatory, and anti-pyroptotic effects. In the present study, rat model of TLE was induced by intrahippocampal kainate and animals received ALC (100 mg/kg, p.o.). ALC properly attenuated intensity of seizures and also incidence of kainate-induced status epilepticus (SE). As well, obtained findings showed that ALC can partially reverse hippocampal levels of MDA, ROS, SOD, TNFa, NF-kB, TLR4, GFAP, and caspase 1. Besides, treatment of kainate group with ALC exerted a protective effect against CA1 neuronal loss and abnormal mossy fiber sprouting (MFS). Conclusively, these results suggest that ALC is capable to attenuate kainate-induced SE which is somewhat mediated through its lowering of oxidative stress, neuroinflammation, and pyroptosis that are related to its neuroprotective effect.

Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection.

OBJECTIVES: Antiretroviral toxic neuropathy (ATN) is associated with dideoxynucleoside reverse transcriptase inhibitor use in patients infected with HIV, possibly as a result of mitochondrial toxicity. Acetyl-l-carnitine (ALC) has been linked to symptomatic improvement in ATN. We present an open-label single-arm pilot study to evaluate changes in intra-epidermal nerve fibre (IENF) density and mitochondrial DNA (mtDNA) copies/cell among subjects treated with 3000 mg ALC daily. METHODS: Punch skin biopsies were examined at baseline and after 24 weeks of therapy. Participants reported neuropathic symptoms using the Gracely Pain Intensity Score. Neurological examinations were completed. RESULTS: Twenty-one subjects completed the study. ALC was generally well tolerated. The IENF density did not change in cases completing 24 weeks of ALC therapy, with median (90% confidence interval) IENF changes of -1.70 (-3.50, infinity) (P=0.98) and 2.15 (-0.10, infinity) (P=0.11) for the distal leg and proximal thigh, respectively. Fat mtDNA copies/cell did not change with therapy. Improvements in neuropathic pain (P<0.01), paresthesias (P=0.01), and symptoms of numbness (P<0.01) were noted. Similarly, improvement was noted on the Gracely Pain Intensity Score. CONCLUSIONS: ALC therapy coincided with improvements in subjective measures of pain in this open-label single-arm study. However, changes were not observed in objective measures of IENF density or mtDNA levels, providing little objective support for use of ALC in this setting.

Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial.

OBJECTIVE: To determine whether acetyl-L-carnitine (ALC), a metabolite necessary for energy metabolism and essential fatty acid anabolism, might help attention-deficit/hyperactivity disorder (ADHD). Trials in Down's syndrome, migraine, and Alzheimer's disease showed benefit for attention. A preliminary trial in ADHD using L-carnitine reported significant benefit. METHOD: A multi-site 16-week pilot study randomized 112 children (83 boys, 29 girls) age 5-12 with systematically diagnosed ADHD to placebo or ALC in weight-based doses from 500 to 1500 mg b.i.d. The 2001 revisions of the Conners' parent and teacher scales (including DSM-IV ADHD symptoms) were administered at baseline, 8, 12, and 16 weeks. Analyses were ANOVA of change from baseline to 16 weeks with treatment, center, and treatment-by-center interaction as independent variables. RESULTS: The primary intent-to-treat analysis, of 9 DSM-IV teacher-rated inattentive symptoms, was not significant. However, secondary analyses were interesting. There was significant (p = 0.02) moderation by subtype: superiority of ALC over placebo in the inattentive type, with an opposite tendency in combined type. There was also a geographic effect (p = 0.047). Side effects were negligible; electrocardiograms, lab work, and physical exam unremarkable. CONCLUSION: ALC appears safe, but with no effect on the overall ADHD population (especially combined type). It deserves further exploration for possible benefit specifically in the inattentive type.

Acetyl-L-carnitine (ALCAR) to enhance nerve regeneration in carpal tunnel syndrome: study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common form of peripheral nerve injury, affecting approximately 3 % of the population. While surgery is effective in mild and moderate cases, nerve and functional recovery are often not complete in severe cases. Therefore, there is a need for adjuvant methods to improve nerve regeneration in those cases. Acetyl-L-carnitine (ALCAR) is involved in lipid transport, vital for mitochondrial function. Although it has been shown to be effective in various forms of neuropathies, it has not been used in traumatic or compressive peripheral nerve injury. METHODS: In this pilot study we will utilize a double-blind, randomized, placebo-controlled design. Inclusion criteria will include adult patients with severe CTS. This will be confirmed by nerve conduction studies and motor unit number estimation (MUNE). Only those with severe motor unit loss in the thenar muscles (2 standard deviations [SD] below the mean for the age group) will be included. Eligible patients will be randomized to receive 3,000 mg/day of ALCAR orally or placebo following carpal tunnel release surgery for 2 months. The primary outcome will be MUNE with supplementary secondary outcome measures that include: 1) two-point discrimination; 2) Semmes-Weinstein monofilaments for pressure sensitivity; 3) cold and pain threshold for small fiber function; 4) Boston self-assessment Carpal Tunnel Questionnaire and 5) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire for symptom severity; and 6) Purdue Pegboard Test for hand functional performance. To follow post treatment recovery and monitor safety, patients will be seen at 3 months, 6 months and 1 year. The outcome measures will be analyzed using two-way ANOVA, with treatment assignment and time points being the independent factors. If significant associations are detected, a post hoc analysis will be completed. We aim to recruit ten patients into each of the two groups. Data from this pilot will provide the basis for power calculation for a full-scale trial. DISCUSSION: ALCAR is a physiologic peptide crucial for fatty acid transport. ALCAR has been shown to be effective in neuroprotection in the central nervous system and increase peripheral nerve regeneration. This has been applied clinically to various systemic peripheral neuropathies including diabetic neuropathy, antiretroviral toxic neuropathy, and chemotherapy-induced peripheral neuropathy. While animal evidence exists for the benefit of ALCAR in compression neuropathy, there have been no human studies to date. This trial will represent the first use of ALCAR in peripheral nerve injury/compression neuropathy. TRIAL REGISTRATION: NCT02141035 ; 20 April 2015.

A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy.

AIMS AND BACKGROUND: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. METHODS AND STUDY DESIGN: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die i.v. infusion over 1-2 h for at least 10 days. RESULTS: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. CONCLUSIONS: Our preliminary results should be confirmed in double-blind, placebo controlled studies.

[A controlled randomized trial of the use of combined L-carnitine and acetyl-L-carnitine treatment in men with oligoasthenozoospermia].

OBJECTIVE: To determine the efficacy and safety of combined L-carnitine and acetyl-L-carnitine therapy in infertile males with oligoasthenozoospermia. METHODS: One hundred fifty patients with oligoasthenozoospermia were randomized selected into treatment and control groups. The treatment group with 90 patients were given L-carnitine (2 g/d) and acetyl-L-carnitine (1 g/d) orally, twice a day. The patients in control group were given Vitamin E 100 mg plus Vitamin C 100 mg, tid. The oral therapy lasted three months and patients accepted sperm analysis every one month. The L-carnitine level in seminal plasma was examined by high performance liquid chromatography (HPC). Side effects as well as pregnant rate were observed. RESULTS: In the treatment group, 85 patients out of 90 finished the three month treatment. Female spouses of 10 patients (11.6%) achieved pregnancy. Moreover, their forward motile sperm per ejaculation, total motile sperm, as well as the concentration of L-carnitine in seminal plasma were increased significantly (P < 0.01). In control group, 53 patients out of 60 completed three months therapy. Two pregnancy (3.7%) was observed. Though some increase was seen in number of forward motile sperm and total motile sperm per ejaculation, the changes were not statistically significant (P > 0.05). The difference of the pregnant rate between two groups was statistically significant. No side effects were found. CONCLUSION: Combined treatment with L-carnitine and acetyl-L-calmitine can be an effective and safe option for treating oligoasthenozoospermia by means of significantly improving forward motile sperm and total motile sperm per ejaculation, as well as increasing pregnant rates.

A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease.

A 1-year, double-blind, placebo-controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treatment. The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. Overall, both ALCAR- and placebo-treated patients declined at the same rate on all primary and most secondary measures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly. However, these preliminary findings are based on past hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.

Long-term acetyl-L-carnitine treatment in Alzheimer's disease.

In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

Selegiline versus L-acetylcarnitine in the treatment of Alzheimer-type dementia.

Forty elderly patients (13 men and 27 women, aged 56 to 80 years) were enrolled in a single-blind, randomized, parallel study to assess the efficacy and safety of selegiline (10 mg, once daily) and that of L-acetylcarnitine (500 mg, twice daily) in the treatment of patients with mild-to-moderate Alzheimer-type disorders. The treatments lasted 90 days, after a run-in period of 15 days. An extensive psychometric examination, carried out at baseline and subsequently at every 30 days of treatment, was used for evaluation of efficacy. Drug safety was assessed by noting any adverse effects that occurred during treatment and by performing laboratory tests at the beginning and end of treatment. According to the resulting data, selegiline therapy led to a global improvement in the capacity for the processing, storage, and retrieval of given information. Improvements in verbal fluency and visuospatial abilities were also noted. The marked between-group differences demonstrate that, at the dosage used, selegiline was far more effective than L-acetylcarnitine with respect to the degree of improvement. Finally, tolerability of both drugs was excellent, inasmuch as neither the monitoring for adverse drug reactions nor laboratory tests revealed any abnormalities resulting from therapy.