NeuroHeal Improves Muscle Regeneration after Injury.

Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with conservative therapy can be inefficient, leading to a high re-injury rate. In addition, the formation of scar tissue implies an alteration of mechanical properties in muscle. There is still a need for new treatments of the injured muscle. NeuroHeal may be one option. Published studies demonstrated that it reduces muscle atrophy due to denervation and disuse. The main objective of the present work was to assess the potential of NeuroHeal to improve muscle regeneration after traumatic injury. Secondary objectives included characterizing the effect of NeuroHeal treatment on satellite cell biology. We used a rat model of sport-induced injury in the gastrocnemius and analyzed the effects of NeuroHeal on functional recovery by means of electrophysiology and tetanic force analysis. These studies were accompanied by immunohistochemistry of the injured muscle to analyze fibrosis, satellite cell state, and fiber type. In addition, we used an in vitro model to determine the effect of NeuroHeal on myoblast biology and partially decipher its mechanism of action. The results showed that NeuroHeal treatment advanced muscle fiber recovery after injury in a preclinical model of muscle injury, and significantly reduced the formation of scar tissue. In vitro, we observed that NeuroHeal accelerated the formation of myotubes. The results pave the way for novel therapeutic avenues for muscle/tendinous disorders.

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

BACKGROUND: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. AIMS: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. METHODS: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. RESULTS: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. CONCLUSIONS: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.

Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.

There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short-lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron-muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP-43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti-TDP-43 aggregation effect was also confirmed in a cell line expressing TDP-43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

Impact of Acamprosate on Chronic Tinnitus: A Randomized-Controlled Trial.

OBJECTIVES: Tinnitus is a common and distressing otologic symptom, with various probable pathophysiologic mechanisms, such as an imbalance between excitatory and inhibitory mechanisms. Acamprosate, generally used to treat alcoholism, is a glutaminergic antagonist and GABA agonist suggested for treating tinnitus. Thus, we aimed to evaluate the efficacy and safety of acamprosate in the treatment of tinnitus. METHODS: The current randomized-controlled trial study included 20 subjects with chronic tinnitus. After performing psycho-acoustic, psychometric and electrophysiological evaluations, all studied tinnitus subjects were randomly divided into two groups of acamprosate and placebo. The first group received oral acamprosate (two tablets of 333 mg/d, three times a day), whereas the second group was given placebo treatment (two tablets, three times a day). After the first 30 days, all evaluations were repeated for the studied groups just in the same manner before the study. Subsequently, the final results of each evaluation were compared together with the baseline values. RESULTS: Nine studied subjects randomly received acamprosate, whereas eleven others received a placebo. There was no significant improvement in the psycho-acoustic tests, except a decrease was observed in the pitch match of tinnitus (P = .039). For those subjects who were receiving acamprosate, a significant reduction was observed in tinnitus handicap inventory (P = .006), tinnitus questionnaire scores (P = .007), and the visual analog scores (P = .007) compared to the placebo group. There was a significant reduction in Action Potential latency (P = .048) as well as an increase in the amplitude of distortion product otoacoustic emissions at 4 kHz (P = .048). CONCLUSIONS: The study results indicated a subjective relief of tinnitus as well as some degree of the electrophysiological improvement at the level of the cochlear and the distal portion of the auditory nerve among the subjects who received the acamprosate. CLINICAL TRIAL REGISTRATION CODE: IRCT2013121115751N1.

Evidence-Based Pharmacotherapies for Alcohol Use Disorder: Clinical Pearls.

Pathologic alcohol use affects more than 2 billion people and accounts for nearly 6% of all deaths worldwide. There are three medications approved for the treatment of alcohol use disorder by the US Food and Drug Administration (FDA): disulfiram, naltrexone (oral and long-acting injectable), and acamprosate. Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. Baclofen, a γ-aminobutyric acid B receptor agonist used for spasticity and pain, received temporary approval for alcohol use disorder in France. Despite effective pharmacotherapies, less than 9% of patients who undergo any form of alcohol use disorder treatment receive pharmacotherapies. Current evidence does not support the use of pharmacogenetic testing for treatment individualization. The objective of this review is to provide knowledge on practice parameters for evidenced-based pharmacologic treatment approaches in patients with alcohol use disorder.

Very Low Frequency of Drug Therapy of Alcohol Dependence in Germany - Analysis of Data of A Statutory Health Insurance.

Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/-12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.

Adherence Across FDA-Approved Medications for Alcohol Use Disorder in a Veterans Administration Population.

OBJECTIVE: U.S. Food and Drug Administration (FDA)-approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present. METHOD: A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%-100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes. RESULTS: A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05). CONCLUSIONS: These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone.

Therapeutic Drug Monitoring of Naltrexone and 6ß-Naltrexol During Anti-craving Treatment in Alcohol Dependence: Reference Ranges.

AIMS: Aim of this study was to associate concentration of naltrexone and its major active metabolite 6ß-naltrexol in blood with therapeutic outcome during treatment with naltrexone in subjects with alcohol dependence. Treatment with the µ-opiate receptor antagonist naltrexone has been shown to reduce craving for alcohol and alcohol intake in patients suffering from alcohol dependence. SHORT SUMMARY: This article shows the use of therapeutic drug monitoring in alcohol dependent patients, who are treated with naltrexone. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. METHODS: Naltrexone and 6ß-naltrexol were analysed by high performance liquid chromatography with column switching and spectrophotometric detection. Alcohol craving was assessed with the Obsessive-Compulsive Drinking Scale (OCDS). RESULTS AND CONCLUSIONS: The study included 43 patients who were treated with naltrexone with a dose of 50 mg/day. Blood was taken for drug analysis 8 h after the last dose of the day at Week 4, 8 and 12. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. Defining patients with OCDS reduction of 70% or higher as responders, the mean±SD concentration of naltrexone plus naltrexol was 22 ± 13 ng/ml compared to 15 ± 8 ng/ml in patients with score reductions of 1-69%. Further analyses indicated that concentrations of 17-50 ng/ml at 8 h and 7-20 ng/ml at 24 h after drug intake were required for treatment response. CONCLUSIONS: Since plasma concentration of naltrexone plus 6ß-naltrexol was found to be predictive for reduction of alcohol craving, it is concluded that therapeutic drug monitoring has the potential to enhance naltrexone's moderate therapeutic efficiency in patients with alcohol dependence.

Use of drugs for alcohol use disorder in Norway 2004­16. / Bruk av medikamenter for alkoholbrukslidelser i Norge 2004­16.

BACKGROUND: Alcohol use disorder can lead to serious illness and early death. The lifetime prevalence rate among the Norwegian population is estimated at 7-10 %. Many patients are never admitted to any kind of treatment programme, and it is assumed that few of those who are treated receive medicinal treatment. There are a variety of drugs on the market that can help reduce alcohol consumption and maintain abstinence. We wanted to gain an insight into the prescription prevalence rate and practice for these drugs. MATERIAL AND METHOD: We obtained encrypted data from the Norwegian Prescription Database of everyone who received drugs for alcohol use disorder in the period 2004-2016. The drugs included were disulfiram, acamprosate, naltrexone 50 mg and nalmefene. RESULTS: The annual prescription prevalence rate increased from 0.85 to 1.13 per 1000 during the observation period. Half of all patients only received prescribed drugs once, and Disulfiram was the most commonly prescribed drug. There was a slight increase in the prevalence rate in age groups up to and including 55 years, and a significant increase for the over-55s. CONCLUSION: There was a slight increase in the prescription prevalence rate during the observation period. Disulfiram was the most commonly prescribed drug. The prescription increase was greatest among women and in the group of over-55s.

Risk of hospitalisation and death related to baclofen for alcohol use disorders: Comparison with nalmefene, acamprosate, and naltrexone in a cohort study of 165 334 patients between 2009 and 2015 in France.

PURPOSE: Baclofen is widely used off-label for alcohol use disorders (AUD) in France, despite its uncertain efficacy and safety, particularly at high doses. This study was designed to evaluate the safety of this off-label use compared to the main approved drugs for AUD (acamprosate, naltrexone, nalmefene). METHODS: This cohort study from the French Health Insurance claims database included patients, aged 18 to 70 years, with no serious comorbidity (assessed by the Charlson score) initiating baclofen or approved drugs for AUD between 2009 and 2015. The risk of hospitalisation or death associated with baclofen, at variable doses over time (from low doses <30 mg/day to high doses ≥180 mg/day), compared to approved drugs, was evaluated by a Cox model adjusted to sociodemographic and medical characteristics. RESULTS: The cohort included 165 334 patients, 47 614 of whom were exposed to baclofen. Patients exposed to baclofen differed from those treated with approved drugs in terms of sociodemographic and medical characteristics (more females, higher socioeconomic status, fewer hospitalisations for alcohol-related problems), but these differences tended to fade at higher doses of baclofen. Baclofen exposure was significantly associated with hospitalisation (hazard ratio [HR] = 1.13 [95%CI: 1.09-1.17]) and death (HR = 1.31 [95%CI: 1.08-1.60]). The risk increased with dose, reaching 1.46 [1.28-1.65] for hospitalisation and 2.27 [1.27-4.07] for death at high doses. Similar results were in patients with a history of hospitalisation for alcohol-related problems. CONCLUSIONS: This study raises concerns about the safety of baclofen for AUD, particularly at high doses, with higher risks of hospitalisation and mortality than approved drugs.

Precision Medicine in Alcohol Dependence: A Controlled Trial Testing Pharmacotherapy Response Among Reward and Relief Drinking Phenotypes.

Randomized trials of medications for alcohol dependence (AD) often report no differences between active medications. Few studies in AD have tested hypotheses regarding which medication will work best for which patients (ie, precision medicine). The PREDICT study tested acamprosate and naltrexone vs placebo in 426 randomly assigned AD patients in a 3-month treatment. PREDICT proposed individuals whose drinking was driven by positive reinforcement (ie, reward drinkers) would have a better treatment response to naltrexone, whereas individuals whose drinking was driven by negative reinforcement (ie, relief drinkers) would have a better treatment response to acamprosate. The goal of the current analysis was to test this precision medicine hypothesis of the PREDICT study via analyses of subgroups. Results indicated that four phenotypes could be derived using the Inventory of Drinking Situations, a 30-item self-report questionnaire. These were high reward/high relief, high reward/low relief, low reward/high relief, and low reward/low relief phenotypes. Construct validation analyses provided strong support for the validity of these phenotypes. The subgroup of individuals who were predominantly reward drinkers and received naltrexone vs placebo had an 83% reduction in the likelihood of any heavy drinking (large effect size). Cutoff analyses were done for clinical applicability: individuals are reward drinkers and respond to naltrexone if their reward score was higher than their relief score AND their reward score was between 12 and 31. Using naltrexone with individuals who are predominantly reward drinkers produces significantly higher effect sizes than prescribing the medication to a more heterogeneous sample.

Metabolomics biomarkers to predict acamprosate treatment response in alcohol-dependent subjects.

Precision medicine for alcohol use disorder (AUD) allows optimal treatment of the right patient with the right drug at the right time. Here, we generated multivariable models incorporating clinical information and serum metabolite levels to predict acamprosate treatment response. The sample of 120 patients was randomly split into a training set (n = 80) and test set (n = 40) five independent times. Treatment response was defined as complete abstinence (no alcohol consumption during 3 months of acamprosate treatment) while nonresponse was defined as any alcohol consumption during this period. In each of the five training sets, we built a predictive model using a least absolute shrinkage and section operator (LASSO) penalized selection method and then evaluated the predictive performance of each model in the corresponding test set. The models predicted acamprosate treatment response with a mean sensitivity and specificity in the test sets of 0.83 and 0.31, respectively, suggesting our model performed well at predicting responders, but not non-responders (i.e. many non-responders were predicted to respond). Studies with larger sample sizes and additional biomarkers will expand the clinical utility of predictive algorithms for pharmaceutical response in AUD.