Treatment Of Alcohol Dependence Research Articles

Tumor specific in situ synthesis of therapeutic agent for precision cancer therapy

BackgroundTraditional chemotherapeutic agents suffer from a lack of selectivity, poor targeting ability, and drug resistance. Developing tumor-specific therapies is crucial for precisely eliminating tumors while circumventing toxicity to normal tissues. Disulfiram (DSF), an FDA-approved drug for treating alcohol dependence, exhibits antitumor effect by forming complexes with copper ions (Cu(DDC)2). Here, we developed a Cu-doped polydopamine-based nanosystem (DSF@CuPDA-PEGM) to achieve in situ generation of toxic Cu(DDC)2.ResultsIn cancer cells with elevated H2O2 contents, CuPDA responsively degrades to release Cu ions and DSF, allowing on-site synthesis of Cu(DDC)2 with potent antitumor activity. DSF@CuPDA-PEGM exhibits excellent therapeutic efficacy against both drug-sensitive and drug-resistant cancer cells while minimizing toxicity to noncancerous cells. Moreover, DSF@CuPDA-PEGM promotes the immune response by inducing cancer cell immunogenic death, thereby augmenting anti-PD-1-based immune checkpoint blockade therapy.ConclusionA tumor-specifically degradable Cu-doped polydopamine-based nanosystem is developed to achieve in situ synthesis of antitumor compounds, providing a promising approach to precisely eliminate tumors and heighten chemo-immunotherapy.Graphical

Synthesis and Catalytic Activity of Novel Complexes Based on Cyano-Substituted Phthalocyanines as Promising Drug Conversion Agents

This paper presents the results of obtaining new cobalt and zinc complexes based on dicyanophenoxy-substituted carboxypthalocyanine. The original method of synthesis and isolation of the compound is shown; its spectroscopic and photophysical characteristics are studied. Studies show the absence of aggregation processes in organic media for solutions of complexes in working concentration ranges. This shows the possibility of the practical application of structures as catalysts. The high catalytic activity of cobalt complexes with dicyanophenoxy-substituted carboxyphthalocyanine ligand in the conversion reaction of sodium diethyldithiocarbamate to disulfiram, which is an active component of drugs for the treatment of alcohol dependence, is determined.

Alcohol does not impact chronic hepatitis C treatment outcomes but increases risk for progressive liver disease: Findings from a prospective multicentre Australian study (OPERA-C).

Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.

Disulfiram-induced psychosis still an important clinical entity: A case series

Disulfiram, an FDA-approved medication for treating alcohol dependence syndrome (ADS), is often used surreptitiously, resulting in severe adverse drug reactions such as disulfiram-induced psychosis (DIP). DIP presents diagnostic challenges, despite being perceived as common; however, there is limited literature available on DIP in India. We describe four cases with a history of psychosis in the background of disulfiram exposure. Our four male patients, aged 30–46 years old, had a history of ADS ranging from 7 to 16 years. They developed DIP after 5–15 days of exposure to disulfiram in doses ranging from 500 to 750 mg. In all cases, disulfiram was administered surreptitiously based on advice from non-experts. Predominant symptomatology included delusion, followed by perceptual disturbances. Naranjo adverse drug reaction probability scale was applied to establish disulfiram as the probable cause of psychosis in all cases. All patients responded to disulfiram discontinuation and a brief period of low-dose antipsychotic therapy within 7 days. The probability of DIP should be explored in a case of ADS presenting with an acute psychotic episode. Disulfiram, though an effective agent, should be used cautiously in selected cases at the recommended dose. Awareness building among family members may prevent and aid in the early detection of DIP.

Alcohol Abstinence, Adherence, and Attitudes toward Disulfiram Treatment for Alcohol Dependence among Patients Attending a Tertiary Care Setting in North India.

Disulfiram is the first Food and Drug Administration (FDA)-approved drug for the treatment of alcohol dependence, primarily acting as a deterrent agent. The available literature on disulfiram treatment for alcohol dependence among individuals in low-income and middle-income countries is scarce, while numerous factors impact the acceptance and adherence to such treatment. The study utilized a purposive sampling methodology. The participants were contacted by telephone at 4 weeks, 12 weeks, and 24 weeks after the initiation of disulfiram treatment. Alcohol abstinence was calculated using the self-reported total alcohol-free days, and adherence and attitudes toward disulfiram treatment were measured using the Treatment Compliance Assessment Scale (TCAS). The participants had a mean age of 39.30±7.7 years. Nearly 62% and 46% of the subjects reported maintenance of alcohol abstinence after initiation of 12 and 24 weeks of disulfiram treatment, respectively. The proportion of non-adherent subjects increased from 36.3% to 57.2% during the 12-week and 24-week follow-up periods. Attitudes toward disulfiram treatment varied significantly across different time points. A strong positive correlation was observed in the alcohol abstinence, adherence, and attitude scores at different time points (P<0.01). The present study's findings unveiled that nearly 60% and 40% of the study subjects were maintaining alcohol abstinence and adherence at 12 weeks and 24 weeks after initiation of disulfiram treatment, respectively. Disulfiram could be a viable psychological tool for alcohol abstinence, but objective measurements are required to underpin its utility in this setting.

A smartphone app-based intervention combined with face-to-face sessions for alcohol dependence at internal medicine clinics: A randomized controlled trial

BackgroundAddressing the limited access to treatments for alcohol dependence, we developed ALM-002, a therapeutic application to be “prescribed” for non-abstinence-oriented treatment in internal medicine settings. Our objective was to preliminarily assess the efficacy and safety of ALM-002. MethodsIn a multicenter, open-label randomized controlled trial, participants aged ≥20 with alcohol dependence and daily alcohol consumption exceeding 60 g for men and 40 g for women, without severe complications, were randomly assigned to either the intervention group using ALM-002 or the treatment-as-usual control group. Participant in both groups received individual face-to-face sessions by physicians at weeks 0, 4, 8, and 12. The primary endpoint was the change in heavy drinking days (HDDs) from week 0 to week 12. A mixed model for repeated measures was employed. ResultsWe enrolled 43 participants: 22 in the intervention group and 21 in the control group. A significant reduction in HDDs every 4 weeks from week 0 to week 12 was observed, with a between-group difference of −6.99 days (95% CI: −12.4 to −1.6 days, standardized mean difference: −0.80). ConclusionsThese results indicate the potential of ALM-002 as a viable treatment for alcohol dependence. Further studies are needed to evaluate the clinical potential of ALM-002.

Cognitive Alterations Associated with Remission and Alcohol Dependence Severity in Ethnically Diverse Patients of Siberia.

Impaired cognition in individuals with alcohol dependence may be associated with increased relapse risk. It has been recorded in more than half of patients during six months after treatment. In certain ethnic groups, for example, Tuvinians, the indigenous people of Siberia, relapses occur in extremely short periods of one to three months after treatment. An approach currently used to alcohol dependence treatment may be less effective for these patients. The study aimed to investigate cognitive sequelae in indigenous Tuvinian patients with alcohol dependence. The sample included 166 patients, 74 of indigenous ethnicity (Tuvinians) and 92 non-indigenous white patients. Data on inhibitory control, cognitive flexibility, attention, and working memory were collected from all the patients and processed using cluster analysis. The clustering data were then complemented by indicators of disorder dynamics, impulsivity, and emotion regulation. The clustering procedure revealed groups with severe cognitive sequelae. More than four-fold attention decrease was found in 43.5% of non-indigenous patients, and more impaired cognitive flexibility was revealed among 60.8% of indigenous patients. Groups with severe cognitive sequelae had higher impulsivity, maladaptive emotion regulation, more hospitalizations, faster disease progression, and shorter remissions. The latter was significantly reduced to 90 days on average in the severe group of indigenous patients versus 135 days of remission in the non-indigenous severe group. Results obtained may advance tailored intervention in alcohol-dependent patients of the indigenous Tuvinian ethnicity. While little is still known about the alcohol dependence course and consequences in the indigenous Tuvinians of Siberia, this study contributes to the global mental health data on alcohol abuse and dependence in indigenous communities.

Alcohol use disorder research in India: An update.

Despite alcohol use being a risk factor for numerous health-related conditions and alcohol use disorder (AUD) recognized as a disease, there was limited research in India until 2010. This narrative review aims to evaluate AUD-related research in India from 2010 to July 2023. A PubMed search used key terms for AUD in India after 2010. Indian and international journals with regional significance that publish alcohol-related research were searched by each author individually. These were then collated, and duplicates were removed. In addition, we also conducted a gray literature search on focused areas related to AUD. The alcohol-related research in India after 2010 focused on diverse areas associated with alcohol use. Some areas of research have received more attention than others. Two major epidemiological surveys conducted in the past decade reveal that around 5% have a problematic alcohol use pattern. Factors associated with alcohol use, like genetic, neurobiological, psychological, and sociocultural, were studied. The studies focused on the clinical profile of AUD, including their correlates, such as craving, withdrawal, alcohol-related harm, and comorbid psychiatric and medical illnesses. During this period, minimal research was conducted to understand AUD's laboratory biomarkers, course, and prognosis. While there was a focus on generating evidence for different psychological interventions for alcohol dependence in management-related research, pharmacological studies centered on anticraving agents like baclofen. Research on noninvasive brain stimulation, such as rTMS, has shown preliminary usefulness in treating alcohol dependence. Very little research has been conducted regarding alcohol policy. In the past decade, Indian research on alcohol has focused on diverse areas. Epidemiological and psychological management-related research received maximum attention. Considering the magnitude of the alcohol-related burden, it is essential to prioritize research to other less studied areas like pharmacological management of alcohol dependence and alcohol policy.

Pharmacological treatments for alcohol dependence: Evidence on uptake, inequalities and comparative effectiveness from a UK population-based cohort.

We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals with such a diagnosis. Further, we compared the effectiveness of two of the most prescribed medications (acamprosate and disulfiram) for alcohol dependence and assessed whether there is inequality in prescribing either of them. We used a nationwide dataset on prescriptions and hospitalisations in Scotland, UK (N = 19,748). We calculated the percentage of patients receiving alcohol dependence prescriptions after discharge, both overall and by socio-economic groups. Binary logistic regressions were used to assess the odds of receiving any alcohol-dependence prescription and the comparative odds of receiving acamprosate or disulfiram. Comparative effectiveness in avoiding future alcohol-related hospitalisations (N = 11,239) was assessed using Cox modelling with statistical adjustment for potential confounding. Upto 7% of hospitalised individuals for alcohol use disorder received prescriptions for alcohol dependence after being discharged. Least deprived socio-economic groups had relatively more individuals receiving prescriptions. Inequalities in prescribing for alcohol dependence existed, especially across sex and comorbidities: males had 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.96) and those with a history of mental health hospitalisations had 10% (OR 0.90, 95% CI 0.82-0.98) lower odds of receiving prescriptions after an alcohol-related hospitalisation. Prescribing disulfiram was superior to prescribing acamprosate in preventing alcohol-related hospitalisations (hazard ratio ranged between 0.60 and 0.81 across analyses). Disulfiram was relatively less likely prescribed to those from more deprived areas. Inequalities in prescribing for alcohol dependence exists in Scotland with lower prescribing to men and disulfiram prescribed more to those from least deprived areas.

Sodium oxybate – new views on an old candidate This presentation will outline the outcome of a clinical development program, including a Phase 3 study, on sodium oxybate in the treatment of alcohol dependence

Abstract Sodium oxybate (SMO) has shown efficacy in the treatment of alcohol withdrawal syndrome (AWS) and in the maintenance of abstinence in alcohol dependent (AD) patients in a series of pilot randomized controlled trials. SMO is marketed in these indications in Italy and Austria since 1991 and 1999, respectively. To expand access to SMO for the treatment of AD in other EU countries and since regulatory standards have evolved, a clinical development and research project in accordance with regulatory guidelines has been initiated in the maintenance of abstinence to further support the already available data. Phase 2 and 3 studies in AD patients were conducted. Results of this development program showed efficacy of SMO in the maintenance of abstinence in AD patients. Since heterogeneity of SMO treatment effect between studies was identified, various analyses explored the potential moderators of SMO efficacy. SMO efficacy was larger in high-severity AD population and with longer treatment duration. SMO was well tolerated both in regular clinical use and in clinical trials.Disclosure of InterestJ. Guiraud Shareolder of: Vergio, Employee of: Vergio

From wernicke-korsakoff to central pontine myelinolysis: the potentially irreversible risks of alcohol use

Introduction Sustained alcohol intake, when combined with incomplete treatment, can result in chronic structural changes in the Central Nervous System, including generalized cortical and cerebellar atrophy, amnesic syndromes like Korsakoff’s syndrome, and white matter disorders such as Central Pontine Myelinolysis and Marchiafava-Bignami syndrome. It is crucial to prevent these complications due to their potential for irreversible and debilitating consequences. For Wernicke-Korsakoff syndrome, early recognition and thiamine administration for prevention are paramount, as it arises from thiamine deficiency due to malnutrition caused by persistent alcohol use. In the case of Central Pontine Myelinolysis, which is caused by abrupt fluctuations in serum osmolality, controlled sodium correction is essential.ObjectivesThrough a clinical case and a review of published literature, this study aims to reflect on the importance of preventing neurological injuries associated with chronic alcohol consumption, specifically Wernicke-Korsakoff Syndrome and Central Pontine Myelinolysis.Methods A literature review was conducted by searching for articles on PubMed using the terms “Alcohol Use Disorder,” “Wernicke-Korsakoff syndrome,” and “Central pontine myelinolysis.” A clinical case is presented, featuring a 50-year-old patient with alcohol use disorder who developed Wernicke-Korsakoff syndrome and Central Pontine Myelinolysis. Considering this case, we reflect on the primary approaches that could have been beneficial in preventing these complications and propose a straightforward method for doing so.Results A 50-year-old patient presented with poor general condition, characterized by low weight, significant loss of strength in the limbs and arms, and incoherent speech with anterograde amnesia and confabulation. This condition had progressed to a point where the patient could no longer walk, perform basic self-care tasks such as bathing, dressing, and eating independently, underscoring the severity of his condition. The diagnoses of Wernicke-Korsakoff syndrome and Central Pontine Myelinolysis were established based on clinical manifestations and the presence of hyperintense lesions observed in the central pons on T2/FLAIR axial MRI scans. This clinical case highlights the importance of proper and precocious prevention of complications in patients with alcohol use disorder. The foremost step in preventing these complications is to treat alcohol dependence effectively, even when faced with patient resistance. It’s vital to remain vigilant about potential complications and implement suitable prophylactic measures.ConclusionsThe devastating effects of complications arising from Alcohol Use Disorder, such as Wernicke-Korsakoff syndrome and Central Pontine Myelinolysis, underscore the importance of enhanced attention that clinicians should provide when approaching these patients at all clinical interactions.Disclosure of InterestNone Declared

A retrospective study of unexpected deaths with alcohol use disorder from Japanese forensic autopsy cases

BackgroundAlcohol use disorder (AUD) is an important target for prevention of alcohol-related problems. In this study, we analyzed forensic autopsy cases to reveal the characteristics of the living conditions and death situations of individuals with AUD. MethodsWe retrospectively investigated 486 cases with a history of alcohol consumption for which a forensic autopsy was performed from 2012 to 2021 in Yamaguchi prefecture. Judgement of AUD was made using DSM-5. Various factors were compared statistically between AUD and non-AUD cases. ResultsOf the 486 cases, 225 (46.2%) were judged to be AUD, including 89 (18.3%) with advanced AUD, 33 (6.8%) were judged not to be AUD, and a judgement could not be made in the remaining cases. AUD was associated with alcohol consumption prior to death. Only 14.3% of the advanced-AUD cases was in treatment for alcohol dependence. The rates of interpersonal, health, financial and legal problems, receipt of public assistance and an extremely cluttered or hoarding house status were higher in all AUD and advanced AUD cases. Living alone, smoking and BMI were also associated with AUD. ConclusionsMany cases of alcohol-related deaths may have AUD, and persons with AUD who undergo a forensic autopsy commonly have multiple socioeconomic factors that may be associated with isolation that is involved in exacerbation of AUD. Further studies of these associations are needed because early diagnosis and treatment of AUD and support for the patient may lead to reduction of alcohol-related deaths.

Associations of ADH1B and ALDH2 genotypes and alcohol flushing with drinking history, withdrawal symptoms, and ICD-10 criteria in Japanese alcohol-dependent men.

Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2 ) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2 ) alleles in East Asians, we evaluated how the ADH1B / ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD). We evaluated how the ADH1B / ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men. The ADH1B*1/*1 group and ALDH2*1/*1 group were 1-5 years younger than the ADH1B*2 (+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for 'tolerance' and 'withdrawal symptoms'. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1-2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status. The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited.

Bioactive potentialities of Grewia flavescens root extract in the treatment of alcohol dependence: Preliminary phytochemical study

Although the use of plants for medicinal purposes is an ancient practice, there is a perception that in the field of chemical dependency, its role has been and is little studied. With regard to alcohol dependence, the third leading cause of hospitalization in psychiatric hospitals in Mozambique, an ethnobotanical work was carried out in 2018 in the Municipality of Massinga, province of Inhambane, with the aim of identifying with practitioners of traditional medicine, the plants they use in their treatment, having resulted, among other plants, in the identification of Grewia flavescens, from which the need arose, based on phytochemical prospecting and literary framework support, to carry out a study of a preliminary nature on the bioactive potential of the root extract (part indicated in the survey) of Grewia flavescens in the treatment of alcohol dependence. The results showed the presence of Flavonoids, Tannins, Alkaloids, Triterpenoids and Saponins. About this group of bioactives, there is bibliographical evidence that points to the anxiolytic and anti-depressant action of Flavonoids, Saponins and Alkaloids, allowing to infer that these can act as mood stabilizers in patients in the phase of alcohol withdrawal syndrome and craving during treatment, not despite deepening from preclinical studies.

ATPase Copper Transporting Beta (ATP7B) Is a Novel Target for Improving the Therapeutic Efficacy of Docetaxel by Disulfiram/Copper in Human Prostate Cancer.

Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel-resistant mPCa cell lines exhibit lower uptake of cellular copper and uniquely express higher levels of a copper exporter protein ATP7B. Knockdown of ATP7B by silencing RNAs (siRNA) sensitized docetaxel-resistant mPCa cells to the growth-inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in human mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, disulfiram (DSF), an FDA-approved drug for the treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel-resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase-associated protein 2 (Skp2), and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results indicate a copper-dependent nutrient vulnerability through ATP7B exporter in docetaxel-resistant prostate cancer for improving the therapeutic efficacy of docetaxel.

Disulfiraminės psichozės atvejis

Introduction. Disulfiram is one of three medications approved by the Federal Drug Administration (FDA) to treat alcohol dependence. Patients tend to abstain from alcohol to avoid the unpleasant effects of alcohol toxicity. There may be some side effects, the most common of which are drowsiness, unusual tiredness, headache, metallic taste in mouth, skin rashes, decreased libido. Disulfiram induced psychosis is a psychiatric side effect that occurs very rarely.&#x0D; Case report. We report the case of a 33-year-old patient with nearly 15 years history of psychiatric personality disorder and alcohol dependence. Approximately 4 days of alcohol abstinence, as an inpatient he was administered disulfiram. After two weeks, the patient began to feel some side effects. He was admitted to hospital and was diagnosed with disulfiram induced psychosis.&#x0D; Discussion. The effect of disulfiram on alcohol metabolism was noticed in the 1940s. It should be used only by motivated patients who must be fully informed about the alcohol-disulfiram reaction. Disulfiram should only be started after about 10 days of sobriety, and the recommended dosage is 500 mg/day. The drug should be used with caution in people with a history of heart disease, diabetes mellitus, hypothyroidism, cerebral damage, nephritis, liver cirrhosis, epilepsy. Caution is recommended for patients who use benzodiazepines, some antibiotics, anticoagulants, tricyclic antidepressants. There may be some adverse effects, more serious ones include changes in vision, numbness, pain or weakness in the limbs, liver cell damage, peripheral neuropathy, seizures – but these are considered to be very rare. Psychiatric side effects may include mood changes, psychotic reactions, memory impairment. Reliable data is lacking, but cases of disulfiram induced psychosis are considered to be rare. Patients taking disulfiram should be monitored carefully.

Comparative pharmacogenetic study of disulfiram or cyanamide efficacy for alcohol dependence: the key role of dopamine neurotransmission gene polymorphisms

The actual direction of increasing the efficacy of alcohol dependence (AD) treatment is the search for opportunities for individualization of therapy using pharmacogenetic markers to stratify patients in order to select the most optimal therapeutic tactics.Aims. To test an associations of possible pharmacogenetic markers with indicators of the efficacy of disulfiram and cyanamide to stabilize remission in patients with AD.Materials and methods. A pharmacogenetic study was conducted on the basis of a double-blind, randomized, comparative, placebo-controlled clinical study of the efficacy and tolerability of disulfiram and cyanamide in the treatment of alcohol dependence syndrome. The main outcome: the duration of retention of patients in the treatment program (in remission), and withdrawal from the treatment program for any reason was considered a negative outcome. Secondary outcomes: time to relapse to alcohol use and time to recurrence to AD. 150 patients with AD (ICD-10 criteria) (av. age - 40.65±1.09 y.o., 19.3% females) were randomly assigned to one of three treatment groups (50 subjects in each): Disulfiram, Cyanamid and Placebo. All patients had weekly (12 weeks) visits to research clinic for brief counselling session. The genetic panel of the study consisted of 15 polymorphic loci in 9 genes: dopamine receptors 2 (DRD2) and 4 (DRD4) types, transmembrane dopamine transporter (DAT), enzymes dopamine-beta-hydroxylase (DBH) and catechol-ortho-methyl-transferase, as well as a two polymorphisms in the genes of the endogenous opioid system and the aldehyde dehydrogenase enzyme gene cluster.Results. For disulfiram, the DBH rs1108580 is associated with a longer remission (p=0.053, trend), and DRD4 VNTR 48 bp is associated with a shorter remission (p=0.006). For cyanamide, DAT VNTR 40 bp was associated with shorter remission (p=0.006) and rapid recurrence to AD (p=0.045). DAT rs27072 has an effect simultaneously in two treatment groups, while the direction of the effect is opposite. For cyanamide, the marker is slightly associated with a longer remission (p = 0.082, trend), a longer time to relapse (p = 0.063, trend) and a longer time to recurrence to AD (p = 0.083, trend). For placebo, DAT rs27072, on the contrary, is associated with a shorter time to to recurrence to AD (p = 0.066, trend). For placebo, DRD2 rs1799732 was associated with a shorter remission (p = 0.001), a shorter time to relapse (p = 0.018), and a shorter time to recurrence to AD (p = 0.001).Conclusion. Preliminary pharmacogenetic markers of the efficacy of alcohol dependence treatment have been identified in genes that control dopaminergic neurotransmission. After independent validation, the obtained genetic markers may be used for pharmacogenetic stratification of patients in order to select the optimal treatment options for alcohol dependence.

Fecal microbiota transplantation repairs intestinal permeability and regulates the expression of 5-HT to influence alcohol-induced depression-like behaviors in C57BL/6J mice.

The epidemic of alcohol abuse affects millions of people worldwide. Relevant evidence supports the notion that the gut microbiota (GM) plays a crucial role in central nervous system (CNS) function, and its composition undergoes changes following alcohol consumption. Therefore, the purpose of this study was to investigate the effect of reconstructing the gut microbiota by fecal microbiota transplantation (FMT) on alcohol dependence. Here, we established an alcohol dependence model with C57BL/6J mice and proved that FMT treatment improved anxiety-like behavior and alcohol-seeking behavior in alcohol-dependent mice. Additionally, we found that the expression of the intestinal intercellular tight junction structure proteins ZO-1 and occludin was significantly increased after FMT. FMT repaired intestinal permeability in alcohol-dependent mice and decreased the levels of lipopolysaccharide (LPS) and proinflammatory factors. Moreover, the serotonin (5-hydroxytryptamine, 5-HT) content was significantly increased in alcohol-dependent mouse intestinal and brain tissues after receiving the fecal microbiome from healthy mice. 16S rRNA sequencing demonstrated that FMT markedly reshaped the composition of the gut microbiota and elicited changes in the intestinal barrier and 5-HT levels. Collectively, our results revealed that FMT has a palliative effect on alcohol dependence and explored the underlying mechanisms, which provides new strategies for the treatment of alcohol dependence.

Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

Current treatments of alcohol use disorder.

Emerging treatments for alcohol dependence reveal an intricate interplay of neurobiological, psychological, and circumstantial factors that contribute to Alcohol Use Disorder (AUD). The approved strategies balancing these factors involve extensive manipulations of neurotransmitter systems such as GABA, Glutamate, Dopamine, Serotonin, and Acetylcholine. Innovative developments are engaging mechanisms such as GABA reuptake inhibition and allosteric modulation. Closer scrutiny is placed on the role of Glutamate in chronic alcohol consumption, with treatments like NMDA receptor antagonists and antiglutamatergic medications showing significant promise. Complementing these neurobiological approaches is the progressive shift towards Personalized Medicine. This strategy emphasizes unique genetic, epigenetic and physiological factors, employing pharmacogenomic principles to optimize treatment response. Concurrently, psychological therapies have become an integral part of the treatment landscape, tackling the cognitive-behavioral dimension of addiction. In instances of AUD comorbidity with other psychiatric disorders, Personalized Medicine becomes pivotal, ensuring treatment and prognosis are closely defined by individual characteristics, as exemplified by Lesch Typology models. Given the high global prevalence and wide distribution of AUD, a persistent necessity exists for development and improvement of treatments. Current research efforts are steadily paving paths towards more sophisticated, effective typology-based treatments: a testament to the recognized imperative for enhanced treatment strategies. The potential encapsulated within the ongoing research suggests a promising future where the clinical relevance of current strategies is not just maintained but significantly improved to effectively counter alcohol dependence.