Long-term Alcohol Treatment Research Articles

Long-term effectiveness of SBIRT by outreach visits on subsequent alcohol treatment utilization among inpatients from general hospital: a 36-months follow-up

Aim To investigate the long-term effect of Screening, Brief Intervention, and Referral to Treatment (SBIRT) on alcohol treatment utilization among general hospital inpatients. Methods This 36-month follow-up of a randomized controlled trial included general hospital inpatients who were screened using the Alcohol Use Disorder Identification Test (AUDIT). Patients with an AUDIT score of 8+ were included. Patients were randomized to either SBIRT (Relay) or treatment as-usual (TAU). Outcome was attendance at a specialized outpatient treatment institution or prescription of pharmacological alcohol treatment in general practice. Using the Danish Civil Registration System, patients were followed in the Danish National Patient Registry, Danish National Alcohol Treatment Register, and the Danish National Prescription Registry. Data was collected up to 36 months after discharge. Results The study population consisted of 258 patients in the Relay group and 303 patients in the TAU group. In the Relay group, 36 (14.0%) patients received treatment versus 23 (7.6%) in the TAU group. Patients in the Relay group had higher odds for receiving treatment compared to the TAU group (OR: 1.97, 95% CI: 1.1–3.4, p = 0.01). Significantly more patients in the Relay group scored 16+ on the AUDIT and had already tried to change their alcohol consumption (both p < 0.01). Adjusted for potential confounders, the effect of the Relay intervention was reduced (OR: 1.37, 95%CI: 0.7–2.5, p = 0.31). Conclusions This study did not find evidence that SBIRT is better than TAU at sustaining significant long-term alcohol treatment utilization after discharge among inpatients from general hospital.

Effect of rifampicin on TLR4-signaling pathways in the nucleus accumbens of the rat brain during abstinence of long-term alcohol treatment.

The treatment with the antibiotic rifampicin (Rif) led to a decrease in the frequency of neurodegenerative pathologies. There are suggestions that the mechanism of action of Rif may be mediated by its effect on toll-like receptor (TLR)4-dependent pathways. We evaluated the expression status of TLR4-dependent genes during abstinence from long-term alcohol treatments in the nucleus accumbens (NAc) of the rat brain, and also studied the effects of Rif to correct these changes. The long-term alcohol treatment was performed by intragastric delivery of ethanol solution. At the end of alcohol treatment intraperitoneal injections of Rif (100mg/kg) or saline were made. Extraction of the brain structures was performed on the 10th day of abstinence from alcohol. We used the SYBR Green qPCR method to quantitatively analyze the relative expression levels of the studied genes. The long-term alcohol treatment promotes an increase in the level of TLR4 mRNA and mRNA of its endogenous ligand high-mobility group protein B1 during abstinence drop alcohol in NAc of rats. The use of Rif in our study led to a decrease in the increased expression of high-mobility group protein B1, Tlr4, and proinflammatory cytokine genes (Il1β, Il6) in the NAc of the rat brain during abstinence of long-term alcohol treatment. In addition, Rif administration increased the decreased mRNA levels of anti-inflammatory cytokines (Il10, Il11). The data obtained indicate the ability of Rif to correct the mechanisms of the TLR4 system genes in the NAc of the rat brain during alcohol abstinence.

Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS), and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1α (HIF-1α), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remain to be elucidated. In this study, we used chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation, and morphology changes, which were reversed by roxadustat. Roxadustat-reduced fatty liver was mainly contributed by the reducing sterol-responsive element-binding protein 1c (SREBP1c) pathway, and enhancing β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophages to hepatocytes, as well as inflammatory cytokine expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol caused ROS generation in the liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro, we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1α regulation. Taken together, our study demonstrates that activation of HIF-1α can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation, and oxidative stress. This study suggested that roxadustat could be a potential drug for ALD treatment.

Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling.

Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress. Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques. We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent. Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.

Involvement of the Distal Fragment of Chromosome 13 in the Regulation of Sensitivity to Ethanol in Mice

The role of the fragment 57-65 cM of mouse chromosome 13 was studied in the regulation of ethanol action on locomotor activity, anxiety and sensitivity to hypnotic and hypothermic effects of ethanol. We used male mice of recombinant lines AKR/J and AKR.CBA-D13Mit76C, differing only in this fragment. After acute administration of ethanol only AKR mice showed the increase in the length of traveled distance in the open-field test (p < 0.05), only the AKR.CBA-D13Mit76C mice demonstrated the increase the time spent in the center of open-field arena (p < 0.05). Intact animals of both lines did not differ in sleep duration and intensity of hypothermia induced by injections of high doses of ethanol. At the same time, long-term alcohol treatment led to the weakening of the hypnotic effect of ethanol in the males of both lines compared to intact animals (p < 0.01 for the AKR, p < 0.001 for AKR.CBA-D13Mit76C). Chronic alcoholization led to increased ethanol-induced hypothermia in AKR males compared to intact animals (p < 0.01) and did not affect the intensity of ethanol hypothermic effect in AKR.CBA-D13Mit76C mice. The results suggest the involvement of the distal fragment 57-65 cM of chromosome 13 in the mechanisms of ethanol action in mice.

Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram

Carbamate kinase from Giardia lamblia is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits G. lamblia CK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here, we examine the structural basis for G. lamblia CK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of giardiasis. The crystal structure of G. lamblia CK soaked with disulfiram revealed that the compound thiocarbamoylated Cys-242, a residue located at the edge of the active site. The modified Cys-242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr-245 side chain against the adenine moiety, an interaction seen in the structure of G. lamblia CK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys-242 in solution. The Giardia viability studies in the metronidazole-resistant strain and the G. lamblia CK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that G. lamblia CK is an attractive drug target for development of novel antigiardial therapies and that disulfiram, an FDA-approved drug, is a promising candidate for drug repurposing.

Alcoholism and coagulating gland: Androgen and insulin like growth factor-1 receptor features

The aim of this work was to characterize the structural and molecular changes in the coagulating gland from rats submitted to long-term alcohol treatment, as well as the possibility of recovery of these parameters after interrupting the alcohol administration. Ten Wistar and twenty UChB rats were divided into: Control group received tap water; Alcoholic group received 10% (v/v) ethanol daily for 150 days; and Abstinent group, received 10% (v/v) ethanol daily for 120 days and then tap water like the control for another 30 days. After 150 days, samples from the coagulating glands were processed for morphological and immunohistochemical analyses. The results showed atrophied epithelium and hypertrophied stroma, especially in the alcoholic group. Intensed androgen receptor (AR) immunolocalization was verified in the epithelium and weak in the stroma of the control group in relation to the other groups. Intensed insulin-like growth factor receptor-1 (IGFR-1) immunolocalization was verified in the stroma of the alcoholic and abstinent groups. Thus, it could be concluded that the excessive alcohol consumption caused morphological and molecular changes in the coagulating gland, characterizing the inverse relation of AR and IGFR-1 localization. The alcohol was an important factor in cellular mitosis occurrence, which could be fundamental element involved in glandular lesions.

Experimental alcoholism and pathogenesis of prostatic diseases in UChB rats

Previous studies have shown that long-term alcohol treatment has negative effects on prostatic stromal-epithelial interaction. Thus, the aim of the present study was to analyze the histochemical, immunohistochemical and ultrastructural alterations that occur in the prostatic stroma and epithelium of rats submitted to chronic alcohol ingestion and alcohol abstinence, as well as to establish the relationship between these changes and prostatic diseases. Thirty male rats (10 Wistar and 20 UChB rats) were divided into three experimental groups: the control group received tap water, the alcoholic group received ethanol diluted to 10 degrees G.L. for 150 days, and the abstinent group received the same liquid diet as the alcoholic group up to 120 days of treatment and only tap water for 30 days thereafter. At the end of treatment, all animals were sacrificed and the ventral lobe of the prostate was removed and processed for histochemical, immunohistochemical and ultrastructural analyses. In addition, plasma testosterone levels were measured. The results showed prostatic intraepithelial neoplasia, infolding of the epithelium towards the stroma, stromal hypertrophy and the presence of inflammatory cells in alcoholic animals. In the abstinent group, alterations were noted mainly in the stromal area. In conclusion, ethanol triggers alterations in prostatic epithelial and stromal compartments, affecting the stromal microenvironment and predisposing the organ to pathological processes.

Dopamine-transporter density in nucleus accumbens of type-1 alcoholics

We have shown that alcoholic patients have a lower number of dopamine transporters in the nucleus accumbens, which mediates the rewarding effects of addictive drugs. Thus, certain dopaminergic agents may be beneficial in the treatment of alcohol withdrawal and in the long-term treatment of alcoholism with selective use.

Prolonged Exposure to Intermittent Alcohol Vapors Blunts Hypothalamic Responsiveness to Immune and Non‐Immune Signals

We have previously shown that long-term alcohol treatment blunts the ACTH response to alcohol itself, as well as to other stresses, and is accompanied by decreased pituitary responsiveness to vasopressin (VP), but not corticotropin-releasing factor (CRF). The present work aims to determine the relevance of changes in CRF and VP receptors in the pituitary gland and/or peptide stores of CRF neurons in the paraventricular nucleus (PVN) of the hypothalamus, the areas that are most directly involved in ACTH release. Intact male rats were exposed to alcohol using a new vapor delivery system which enables individual rat housing in boxes. Alcohol treatment was delivered for 6 hr once daily (0700-1300), after which the rats were returned to their home cages where they had free access to food and water. Control rats were kept in similar boxes, but not exposed to alcohol. Total treatment time was 8 days. All animals were equipped with indwelling jugular cannulae that were used to monitor blood alcohol levels (BALs) as well as ACTH and corticosterone release throughout drug exposure. Due to the presence of a swivel, the animals' movements were not restricted or hindered by the presence of these cannulae. On the morning of day 9, the animals were decapitated under basal conditions or exposed to a neurogenic (mild electrofootshocks) or systemic [i.v. lipopolysaccharide (LPS)] stimulus. PVN neuronal responses, indicated by changes in mRNA concentrations of the immediate early genes (IEGs) c-fos and NGFI-B, and plasma ACTH levels were measured before and during endotoxemia or electrofootshocks. In the absence of alcohol, plasma ACTH and corticosterone remained at basal levels, indicating the absence of environment-induced stress. In rats exposed to alcohol, BALs were consistent and predictable, and we targeted peak values of about 200 mg%. At the end of the drug treatment period, there were no significant differences between CRF and VP receptor mRNA levels in the anterior pituitary of control and alcohol-treated rats. In contrast, alcohol treatment respectively decreased CRF and increased VP stores in the external zone of the median eminence. It also increased NGFI-B and c-fos transcripts in the magnocellular (m) portion of the PVN, but not the parvicellular (p) division of this nucleus under basal conditions (i.e., in the absence of shocks or LPS). After exposure to these stressors, on the other hand, all groups of rats showed significant increases in plasma ACTH levels as well as up-regulation of their PVN neuronal response, as indicated by changes in pPVN IEGs transcripts. However, these hormonal and neuronal responses were significantly blunted in animals pretreated with alcohol. Collectively, our results suggest that decreased PVN neuronal activation represents an important mechanism of the ability of long-term alcohol treatment to blunt the ACTH response to shocks or endotoxemia. In addition, the new system of alcohol delivery that we developed is practical and reliable, and has the significant advantage that it enables measurement of circulating hormone levels during drug exposure of the animals.

Benzodiazepine treatment for alcohol-dependent patients.

Benzodiazepines (BZDs) are the preferred pharmacological agents for treatment of acute alcohol withdrawal. Treatment with BZDs can be administered on an out-patient basis for subjects experiencing mild to moderate withdrawal and on an in-patient basis for the most severe forms of withdrawal. The efficacy of BZDs for long-term treatment of alcoholism has been more controversial. Controlled studies indicate that BZD treatment does not improve abstinence rate. Most reviews of drug treatment of alcoholism conclude that routine use of BZDs is not indicated on a long-term basis. However, the clinical reality is that many alcoholics are treated by BZDs during detoxification and then continue to receive them for the treatment of anxiety disorders or insomnia, often secondary to alcohol dependence. After a review of the biological properties of BZDs related to their therapeutic issues, this review discusses the major indications for BZD treatment of alcoholism. BZDs are first prescribed to prevent and treat symptoms of alcohol withdrawal. Indication of BZD administration during alcohol withdrawal and criteria of choice of an agent according to its half-life or its route of administration are discussed. The different protocols of BZD treatment during withdrawal are considered (e.g. loading techniques, symptom-triggered therapy). The use of BZDs in the treatment of anxiety associated with alcohol dependence is examined. Among unwanted effects, risk of abuse, memory impairment, confusion, and delirium are described. Finally, practical guidelines for the use of BZDs in the treatment of alcoholism are proposed.

Consider tiapride for long-term treatment of alcoholism

Consider tiapride for long-term treatment of alcoholism

Long-term treatment of alcoholism in schizophrenic outpatients

Long-term treatment of alcoholism in schizophrenic outpatients

The response of primary care physicians to problem drinkers.

This study examines the extent and characteristics of primary care physicians' response to their patients' drinking problems and several factors which might impede or facilitate their response. The data were collected in an anonymous questionnaire survey of primary care practitioners in the greater Boston area. Although most had been exposed to some type of alcohol education, few physicians were very confident in their patient management skills and few felt professionally responsible for long-term alcohol treatment. The data suggest that physicians may be reluctant to become involved in treatment they are not prepared to carry out or which they feel is not appropriate to their role. If physicians are to be encouraged to take an active role in the diagnosis and treatment of alcoholism, the emphasis of educational programs should go beyond increasing knowledge and changing attitudes, and focus instead on providing the necessary clinical skills.

Effects of ethanol on blood pressure of normal and hypertensive rats.

Many epidemiological studies have shown an association between heavy drinking and high blood pressure. D'Alonzo and Pell (1) estimated that hypertension was two to three times more common among alcoholics than among controls. A greater incidence of hypertension among heavy drinkers has also been reported in the prospective epidemiological studies of Dyer et al. (2) and Klatsky et al. (3). Gyntelberg and Meyer (4) and Beevets (5) both suggested that heavy drinkers have higher blood pressure than do thbse who do not drink. Experimental studies investigating shortand long-term effects of ethanol on blood pressure have had contradictory results. With short-term administration of ethanol, Grollman (6) observed modest increases in diastolic and systolic pressure in nondrinkers, whereas no effect was observed by Stein et al. (7) and a decrease was shown by Conway (8). Webb and Degerli (9) found an increase in arterial blood pressure in anesthetized ogs given intravenous ethanol. Maines and Aldinger (10) reported hypotension as a consequence of myocardial depression in rats receiving long-term alcohol treatment. The present study was performed to investigate blood pressure changes in rats given ethanol solution as the only fluid. Spontaneously hypertensive rats and genetically related normotensive controls were used in an attempt to observe the effect of ethanol on the development of high blood pressure.

Long-Term Treatment of Alcoholism with Amitriptyline and Emylcamate. A Double-Blind Evaluation

Long-Term Treatment of Alcoholism with Amitriptyline and Emylcamate. A Double-Blind Evaluation