-
Neuropsychopharmacology : Official... Nov 2021Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these... (Meta-Analysis)
Meta-Analysis
Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E-8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E-8; acamprosate TR: rs77583603, p = 3.1E-9). The top association signal for TR (p = 7.7E-8) and second strongest signal in the THR (p = 6.1E-8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p = 3.7E-4) and THR (p = 2.6E-4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.
Topics: Alcohol Deterrents; Alcoholism; Female; Genome-Wide Association Study; Humans; Male; Naltrexone; Narcotic Antagonists; Pharmacogenetics; Taurine; Treatment Outcome
PubMed: 34302059
DOI: 10.1038/s41386-021-01097-0 -
Pharmaceutics Apr 2020Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to...
Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug-Drug Interactions.
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of ) and OAT3 (gene product of ) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with or . Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated -aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a K-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a K-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3.
PubMed: 32344570
DOI: 10.3390/pharmaceutics12040390 -
Der Nervenarzt Jan 2021So far few medications are approved for prophylactic treatment of alcohol dependence relapse. Apart from disulfiram, which is no longer marketed in Germany, the opioid... (Review)
Review
So far few medications are approved for prophylactic treatment of alcohol dependence relapse. Apart from disulfiram, which is no longer marketed in Germany, the opioid antagonists naltrexone, nalmefene and the putative glutamate antagonist acamprosate are approved. In some other countries, baclofen and gamma-hydroxybutyrate (GHB) are licensed. Possible other drugs of interest for prophylaxis of alcohol dependence relapse are vareniclin, gabapentin, and topiramate, but so far none of them have received approval. In the light of the currently running revision of the German guidelines for the diagnosis and treatment of alcohol related disorders, an update on the pharmacotherapy of alcohol dependence is presented.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Germany; Humans; Naltrexone; Narcotic Antagonists; Taurine
PubMed: 32696076
DOI: 10.1007/s00115-020-00954-5 -
Frontiers in Pharmacology 2020Selective serotonin reuptake inhibitors (SSRIs) are a standard of care for the pharmacotherapy of patients suffering from Major Depressive Disorder (MDD). However, only... (Review)
Review
Selective serotonin reuptake inhibitors (SSRIs) are a standard of care for the pharmacotherapy of patients suffering from Major Depressive Disorder (MDD). However, only one-half to two-thirds of MDD patients respond to SSRI therapy. Recently, a "multiple omics" research strategy was applied to identify genetic differences between patients who did and did not respond to SSRI therapy. As a first step, plasma metabolites were assayed using samples from the 803 patients in the PGRN-AMPS SSRI MDD trial. The metabolomics data were then used to "inform" genomics by performing a genome-wide association study (GWAS) for plasma concentrations of the metabolite most highly associated with clinical response, serotonin (5-HT). Two genome-wide or near genome-wide significant single nucleotide polymorphism (SNP) signals were identified, one that mapped near the gene and another across the gene, both genes that are highly expressed in the brain. Knocking down TSPAN5 and ERICH3 resulted in decreased 5-HT concentrations in neuroblastoma cell culture media and decreased expression of enzymes involved in 5-HT biosynthesis and metabolism. Functional genomic studies demonstrated that ERICH3 was involved in clathrin-mediated vesicle formation and was an ethanol-responsive gene that may be a marker for response to acamprosate pharmacotherapy of alcohol use disorder (AUD), a neuropsychiatric disorder highly co-morbid with MDD. In parallel studies, kynurenine was the plasma metabolite most highly associated with MDD symptom severity and application of a metabolomics-informed pharmacogenomics approach identified and as genes associated with variation in plasma kynurenine levels. Both genes also contributed to kynurenine-related inflammatory pathways. Finally, a multiply replicated predictive algorithm for SSRI clinical response with a balanced predictive accuracy of 76% (compared with 56% for clinical data alone) was developed by including the SNPs in , , and . In summary, application of a multiple omics research strategy that used metabolomics to inform genomics, followed by functional genomic studies, identified novel genes that influenced monoamine biology and made it possible to develop a predictive algorithm for SSRI clinical outcomes in MDD. A similar pharmaco-omic research strategy might be broadly applicable for the study of other neuropsychiatric diseases and their drug therapy.
PubMed: 33510640
DOI: 10.3389/fphar.2020.614048 -
Frontiers in Pharmacology 2022Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The...
Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received 3 months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. We performed plasma proteomics using the Olink target 96 inflammation panel and identified that baseline plasma TNF superfamily member 10 (TNFSF10) concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the 3 months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response.
PubMed: 36120372
DOI: 10.3389/fphar.2022.986238 -
Cells Dec 2020Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with...
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.
Topics: Acamprosate; Animals; Athletic Injuries; Cell Line; Drug Combinations; Male; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts; Neuroprotective Agents; Rats; Rats, Wistar; Recovery of Function; Regeneration; Ribavirin
PubMed: 33374379
DOI: 10.3390/cells10010022 -
Alcohol and Alcoholism (Oxford,... Sep 2022To understand service users' views and experiences of alcohol relapse prevention medication, views of a telephone behavioural modification intervention delivered by...
AIMS
To understand service users' views and experiences of alcohol relapse prevention medication, views of a telephone behavioural modification intervention delivered by pharmacists and the use of Contingency Management (CM) to support acamprosate adherence following assisted alcohol withdrawal.
METHODS
Four focus groups were conducted within four alcohol treatment and recovery groups across England (UK), with service users with lived experience of alcohol dependence (26 participants). Semi-structured topic guide was used to explore participants' views and experiences of alcohol relapse prevention medication, a telephone behavioural modification medication intervention delivered by pharmacists, and the use of CM to support acamprosate adherence. These were audio-recorded, transcribed verbatim and thematically analysed inductively and deductively.
RESULTS
Four themes were identified: concerns about support and availability of alcohol relapse prevention medication; lack of knowledge and understanding about acamprosate treatment; positive perceptions of acamprosate adherence telephone support from pharmacists; and negative perceptions of CM to support acamprosate adherence. There were misunderstandings about acamprosate's mode of action and strong negative beliefs about CM. However, most were positive about pharmacists' new role to support acamprosate adherence.
CONCLUSION
This study highlighted challenges service users face to commence alcohol relapse prevention medication. It appears service users could benefit from a pharmacist-led telephone intervention to improve understanding about acamprosate medication, particularly, if delivered in an engaging and motivating way.
Topics: Acamprosate; Alcoholism; Attitude of Health Personnel; Community Pharmacy Services; Humans; Medication Adherence; Pharmacists; Professional Role; Secondary Prevention; Substance Withdrawal Syndrome
PubMed: 35292814
DOI: 10.1093/alcalc/agac011 -
Journal of Substance Abuse Treatment Jan 2023Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access.... (Review)
Review
BACKGROUND
Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access. The objective of this scoping review is to examine models of AUD treatment in primary care that include pharmacotherapy (acamprosate, disulfiram, naltrexone).
METHODS
The team undertook a search across MEDLINE, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, and Web of Science on May 21, 2021. Eligibility criteria included: patient population ≥ 18 years old, primary care-based setting, US-based study, presence of an intervention to promote AUD treatment, and prescription of FDA-approved AUD pharmacotherapy. Study design was limited to controlled trials and observational studies. We assessed study bias using a modified Oxford Centre for Evidence-based Medicine Rating Framework quality rating scheme.
RESULTS
The qualitative synthesis included forty-seven papers, representing 25 primary studies. Primary study sample sizes ranged from 24 to 830,825 participants and many (44 %) were randomized controlled trials. Most studies (80 %) included a nonpharmacologic intervention for AUD: 56 % with brief intervention, 40 % with motivational interviewing, and 12 % with motivational enhancement therapy. A plurality of studies (48 %) included mixed pharmacologic interventions, with administration of any combination of naltrexone, acamprosate, and/or disulfiram. Of the 47 total studies included, 68 % assessed care initiation and engagement. Fewer studies (15 %) explored practices surrounding screening for or diagnosing AUD. Outcome measures included receipt of pharmacotherapy and alcohol consumption, which about half of studies included (53 % and 51 %, respectively). Many of these outcomes showed significant findings in favor of integrated care models for AUD.
CONCLUSIONS
The integration of AUD pharmacotherapy in primary care settings may be associated with improved process and outcome measures of care. Future research should seek to understand the varied experiences across care integration models.
Topics: Humans; United States; Adolescent; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Alcohol Drinking; Primary Health Care; Randomized Controlled Trials as Topic
PubMed: 36332528
DOI: 10.1016/j.jsat.2022.108919 -
Alcohol Research : Current Reviews 2022This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as... (Review)
Review
This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Mason's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.
Topics: United States; Humans; Alcoholism; National Institute on Alcohol Abuse and Alcoholism (U.S.); Alcohol Drinking; Alcohol-Related Disorders; National Institutes of Health (U.S.); Alcohol Deterrents; Naltrexone
PubMed: 36320345
DOI: 10.35946/arcr.v42.1.11 -
Journal of General Internal Medicine Jul 2021Alcohol use disorder (AUD) imposes a high mortality and economic burden. Effective treatment is available, though underutilized.
BACKGROUND
Alcohol use disorder (AUD) imposes a high mortality and economic burden. Effective treatment is available, though underutilized.
OBJECTIVE
Describe trends in AUD pharmacotherapy, variation in prescribing, and associated patient factors.
DESIGN
Retrospective cohort using electronic health records from 2010 to 2019.
PARTICIPANTS
Primary care patients from 39 clinics in Ohio and Florida with diagnostic codes for alcohol dependence or abuse plus social history indicating alcohol use. PCPs in family or internal medicine with at least 20 AUD patients.
MAIN MEASURES
Pharmacotherapy for AUD (naltrexone, acamprosate, and disulfiram), abstinence from alcohol, patient demographics, and comorbidities. Generalized linear mixed models were used to identify patient factors associated with prescriptions and the association of pharmacotherapy with abstinence.
KEY RESULTS
We identified 13,250 patients; average age was 54 years, 66.9% were male, 75.0% were White, and median household income was $51,776 per year. Over 10 years, the prescription rate rose from 4.4 to 5.6%. Patients who were Black (aOR 0.74; 95% CI 0.58, 0.94) and insured by Medicare versus commercial insurance (aOR 0.61; 95% CI 0.48, 0.78) were less likely to be treated. Higher median household income ($10,000 increment, aOR 1.06; 95% CI 1.03, 1.10) and Medicaid versus commercial insurance (aOR 1.52; 95% CI 1.24, 1.87) were associated with treatment. Receiving pharmacotherapy was associated with subsequent documented abstinence from alcohol (aOR 1.60; 95% CI 1.33, 1.92). We identified 236 PCPs. The average prescription rate was 3.6% (range 0 to 24%). The top decile prescribed to 14.6% of their patients. The bottom 4 deciles had no prescriptions. Family physicians had higher rates of pharmacotherapy than internists (OR 1.50; 95% CI 1.21, 1.85).
CONCLUSIONS
Medications for AUD are infrequently prescribed, but there is considerable variation among PCPs. Increasing the use of pharmacotherapy by non-prescribers may increase abstinence from alcohol.
Topics: Aged; Alcoholism; Florida; Humans; Male; Medicare; Middle Aged; Ohio; Primary Health Care; Retrospective Studies; United States
PubMed: 33515195
DOI: 10.1007/s11606-020-06454-1