Betulinic acid-nucleoside hybrid prevents acute alcohol -induced liver damage by promoting anti-oxidative stress and autophagy.

Alcoholic abuse is one of the most serious causes of liver diseases worldwide. Although detailed molecular pathogenesis of alcohol-induced liver damages remains elusive with intensive debates, it has been widely recognized that hepatic damage caused by free radicals generated from alcohol metabolism is one of the most critical factors for alcohol-induced liver diseases. Betulinic acid is a potent antioxidant with additional known pharmacological safety characteristics and minimal toxicity. However, poor solubility limited its usage. In this study, we assessed the efficacy of BAN, a betulinic acid and nucleoside hybrid with good water solubility, in reversing acute liver damages using an established alcohol overdose animal model. The results indicated that BAN is an extremely promising therapeutic agent against acute alcohol-induced liver damage. BAN effectively protects liver from alcohol damage by reducing serum ALT level by up to 47%, as well as liver oxidative stress indicated by significantly increased SOD, CAT, and GSH-Px levels. Moreover, hepatic FXR activation and a corresponding downstream anti-oxidative stress transcriptional cascade including Nrf2, HO-1, and NOQ1 induce the protective role of BAN. On the other hand, BAN administration also leads to increase cellular autophagy response, as indicated by the key ATG protein activation. We concluded that BAN, comparing with Betulinic acid, prevents acute alcohol-induced liver damages more effectively, with the dual mechanisms of neutralizing oxidative stress and promoting autophagy.

Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial.

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.

Prospective memory deficits following acute alcohol consumption.

BACKGROUND: Prospective memory is a critical neurocognitive capacity that refers to the ability to execute delayed intentions. To date, few studies have investigated the effects of acute alcohol consumption on prospective memory, and important questions remain about the mechanisms that might underpin acute alcohol-induced prospective memory impairment. AIMS: The current study sought to clarify the nature and magnitude of prospective memory difficulties following acute alcohol consumption and to test the degree to which any problems with prospective remembering might be a secondary consequence of broader cognitive impairment. This study also investigated whether there were potential sex differences. METHODS: In all, 124 healthy adult social drinkers were assigned to either the alcohol (n = 61) or placebo (n = 63) condition. Participants were administered a dose of 0.6 g/kg alcohol or a matched placebo drink and then asked to complete a measure of prospective memory. A broader neurocognitive test battery was also administered. RESULTS: Relative to the placebo condition, acute alcohol intoxication led to significant impairment on all prospective memory tasks, with effects mostly large in magnitude. These difficulties could not be explained by broader problems in retrospective memory, executive function or episodic future thinking. In addition, females recorded a higher blood alcohol concentration than males; however, no sex differences in prospective memory performance were identified following acute alcohol use. CONCLUSION: The results show that acutely, even a moderate dose of alcohol substantially impairs prospective memory function. These findings have potentially important implications for understanding many of the maladaptive behaviours associated with acute alcohol consumption.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking.

Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol-induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or "priming," altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long-term sequelae may be due to a failure to recover from EtOH-induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and thereby perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents.

A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease.

Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.

Persistence of cerebellar ataxia during chronic ethanol exposure is associated with epigenetic up-regulation of Fmr1 gene expression in rat cerebellum.

BACKGROUND: Alcohol intoxication produces ataxia by affecting the cerebellum, which coordinates movements. Fragile X mental retardation (FMR) protein is a complex regulator of RNA and synaptic plasticity implicated in fragile X-associated tremor/ataxia syndrome, which features ataxia and increased Fmr1 mRNA expression resulting from epigenetic dysregulation of FMRP. We recently demonstrated that acute ethanol-induced ataxia is associated with increased cerebellar Fmr1 gene expression via histone modifications in rats, but it is unknown whether similar behavioral and molecular changes occur following chronic ethanol exposure. Here, we investigated the effects of chronic ethanol exposure on ataxia and epigenetically regulated changes in Fmr1 expression in the cerebellum. METHODS: Male adult Sprague-Dawley rats were trained on the accelerating rotarod and then fed with chronic ethanol or a control Lieber-DeCarli diet while undergoing periodic behavioral testing for ataxia during ethanol exposure and withdrawal. Cerebellar tissues were analyzed for expression of the Fmr1 gene and its targets using a real-time quantitative polymerase chain reaction assay. The epigenetic regulation of Fmr1 was also investigated using a chromatin immunoprecipitation assay. RESULTS: Ataxic behavior measured by the accelerating rotarod behavioral test developed during chronic ethanol treatment and persisted at both the 8-h and 24-h withdrawal time points compared to control diet-fed rats. In addition, chronic ethanol treatment resulted in up-regulated expression of Fmr1 mRNA and increased activating epigenetic marks H3K27 acetylation and H3K4 trimethylation at 2 sites within the Fmr1 promoter. Finally, measurement of the expression of relevant FMRP mRNA targets in the cerebellum showed that chronic ethanol up-regulated cAMP response element binding (CREB) Creb1, Psd95, Grm5, and Grin2b mRNA expression without altering Grin2a, Eaa1, or histone acetyltransferases CREB binding protein (Cbp) or p300 mRNA transcripts. CONCLUSIONS: These results suggest that epigenetic regulation of Fmr1 and subsequent FMRP regulation of target mRNA transcripts constitute neuroadaptations in the cerebellum that may underlie the persistence of ataxic behavior during chronic ethanol exposure and withdrawal.

Effects of prenatal alcohol exposure on cognitive and behavioral development: Findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts.

BACKGROUND: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. METHODS: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. RESULTS: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. CONCLUSIONS: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

Gender moderates the association between acute alcohol intoxication and facial emotion recognition in a naturalistic field study setting.

BACKGROUND: Alcohol intoxication is associated with significant negative social consequences. Social information processing theory provides a framework for understanding how the accurate decoding and interpretation of social cues are critical for effective social responding. Acute intoxication has the potential to disrupt facial emotion recognition. If alcohol impairs the processing and interpretation of emotional cues, then the resultant behavioral responses may be less effective. The current study tested the association between alcohol intoxication and facial emotion recognition in a naturalistic field study of intoxicated participants. METHODS: 114 participants (59.4% men; Mage  = 24.2 years) who had been consuming alcohol were recruited in the downtown area of a mid-size town surrounded by several drinking establishments in the mid-southern United States. Participants were shown images depicting 5 facial displays of emotions (happy, sad, anger, disgust, and no emotion) portrayed by 1 male and 1 female actor per emotion and breath alcohol concentration (BrAC) was measured by the field breathalyzer test (M = 0.078%, SD = 0.052). RESULTS: BrAC was significantly negatively associated with emotion recognition accuracy when controlling for average alcohol use, B = -.35, t = -2.08, p < 0.05, F(3, 110) = 5.28, p < 0.01, R2  = 0.13. A significant BrAC × gender interaction was revealed, B = -0.39, t = -2.07, p = 0.04, ΔR2  = 0.033, p = 0.04, such that men (but not women) displayed a significant negative association between BrAC and emotion recognition accuracy. CONCLUSIONS: Acute intoxication was associated with impaired facial emotion recognition, particularly for men, in a field study context. Findings support and extend some previous experimental laboratory-based research and suggest that intoxication can impair the decoding stage of social information processing.

Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial.

PURPOSE: The trial aimed to investigate the effectiveness of exogenous melatonin as an adjuvant to pregabalin for relief of pain in patients suffering from painful diabetic neuropathy (PDN). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial was carried out between October 2019 and December 2020 in an outpatient specialty clinic in Iran. One-hundred-three type 2 diabetic patients suffering from PDN were randomized into either the melatonin group (n = 52) or the placebo group (n = 51). Besides pregabalin at a dose of 150 mg per day, patients started with melatonin or an identical placebo, at a dose of 3 mg/day at bedtime for 1 week, which was augmented to 6 mg/day for further 7 weeks. The primary outcomes were changes in mean NRS (numerical rating scale) pain score from baseline to endpoint and responder rate (patients with a reduction of 50% and higher in average pain score compared with baseline). Secondary endpoints were changes in mean NRS pain-related sleep-interference score, overall improvement evaluated by Patient and Clinical Global Impressions of Change (PGIC, CGIC), and impact of the intervention on patient's Health-related quality of life (QOL). All analyses were conducted on an Intention-to-Treat (ITT) analysis data set. RESULTS: At the study endpoint, treatment with melatonin resulted in a considerably higher reduction in the mean NRS pain score in comparison with placebo (4.2 ± 1.83 vs. 2.9 ± 1.56; P-value < 0.001). In terms of treatment responders, a greater proportion of melatonin-treated patients satisfied the responder criterion than placebo-treated patients (63.5% vs. 43.1%). Melatonin also reduced pain-related sleep interference scores more than did placebo (3.38 ± 1.49 vs. 2.25 ± 1.26; P-value < 0.001). Further, at the endpoint, more improvement was also seen in terms of PGIC, CGIC, and Health-related QOL in patients treated with melatonin than placebo. Melatonin was also well tolerated. CONCLUSION: The present results showed that melatonin as an adjunct therapy to pregabalin might be helpful for use in patients with PDN. However, confirmation of these results requires further studies.

Successful implementation of managed alcohol programs in the San Francisco Bay Area during the COVID-19 crisis.

Background: The COVID-19 crisis presents new challenges and opportunities in managing alcohol use disorders, particularly for people unable to shelter in place due to homelessness or other reasons. Requiring abstinence for shelter engagement is impractical for many with severe alcohol use disorders and poses a modifiable barrier to self-isolation orders. Managed alcohol programs (MAPs) have successfully increased housing adherence for those with physical alcohol dependence in Canada, but to our knowledge, they have not been implemented in the United States. To avoid life-threatening alcohol withdrawal syndromes and to support adherence to COVID-19 self-isolation and quarantine orders, MAPs were piloted by the public health departments of San Francisco and Alameda counties. Development of MAPs: We describe implementation of a first-in-the-nation alcohol use disorder intervention of a MAP that emerged at three public health isolation settings within San Francisco and Alameda counties in California. All three interventions utilized a similar process to develop the protocol and implement the MAP that included identification of champions for system-level advocacy and engagement of stakeholders. Implementation of MAPs: We describe the creation and implementation of the distinct protocols. We provide examples of iterative changes to workflow processes and key lessons learned pertaining to protocol development, acceptability by stakeholders, alcohol procurement, documentation, and assessment. We discuss safety considerations, noting that there were no deaths or serious adverse events in any of the patients of the MAP during the 2-month implementation period. Conclusions: MAP pilots have been implemented in the US to aid adherence to isolation and quarantine setting guidelines. Lessons learned provide a foundation for their expansion as a recognized public health intervention for individuals with severe alcohol use disorders who are unable to stabilize within existing care systems. Based on the success of MAP implementation, efforts are under way to investigate alcohol management in homeless populations more broadly.

Drug-facilitated sexual assault and other crimes: A systematic review by countries.

Drug-facilitated sexual assault (DFSA) and drug-facilitated crime (DFC) constitute a mode of violence that is generally unknown to the population and may go unnoticed by health professionals. The aim of this systematic review was to analyze the victims of DFC, compiling their sociodemographic characteristics, the toxic substances used and their biological matrices and modes of action, in order to identify the substances that are commonly put to criminal use. The aim would be to establish political and health strategies that inform and warn people about possible criminal social behaviors consequent danger to health. This systematic review was conducted following the PRISMA guidelines. Alcohol, benzodiazepines and cocaine were among the most commonly detected substances. In most of the hospitals, immunoassays, liquid chromatography (LC-MS), or gas chromatography-mass spectrometry (GC-MS) analyses were used to identify the substances, while the most frequently used biological matrices were blood and urine. From a judicial point of view, the instrumental protocols and techniques followed for the detection of toxics in different biological matrices must guarantee the reliability and validity of the results for use in a court of law. The recommendations of international organizations should be followed and must be called upon to strengthen their respective national laws against this chemical submission (CS) phenomenon.

Perigestational alcohol consumption induces altered early placentation and organogenic embryo growth restriction by disruption of trophoblast angiogenic factors.

RESEARCH QUESTION: Maternal alcohol consumption produces fetal retardation and malformations, probably associated with placental defects. Does perigestational alcohol consumption up to organogenesis lead to abnormal placentation and embryo growth restriction by disrupting the vascular endothelial growth factor (VEGF) system in embryo-placental development? DESIGN: Female mice were treated with 10% ethanol in drinking water before and up to day 10 of gestation. Control mice received ethanol-free water. After treatment, the trophoblastic tissue, embryo growth and the angiogenic VEGF pathway were analysed. RESULTS: Female mice who had received treatment had resorbed and delayed implantation sites with poor ectoplacental cone development. Reduced trophoblastic area tissue from female mice who had received treatment had abnormal junctional zone and diminished labyrinthine vascularization. After treatment, the labyrinth had increased chorionic trophoblast proliferation, hypoxia inducible factor-1α immunoexpression but reduced apoptosis. The embryo growth was reduced concomitantly with low VEGF immunostaining but high endothelial nitric oxide synthase (eNOS) expression. In junctional and labyrinth of treated female mice, gene and protein immunoexpression of VEGF was reduced and the protein expression of FLT-1 increased compared with controls. Increased activation of kinase insert domain receptor receptor (phosphorylated KDR) and expression of eNOS were observed in placenta of treated female mice. Immunoexpression of metalloproteinase-9, however, was reduced in junctional zone but increased in labyrinth, compared with controls. CONCLUSIONS: These data reveal inadequate expression of VEGF/receptors and angiogenic eNOS and metalloproteinase factors related to abnormal early placentation after perigestational alcohol ingestion, providing insight into aetiological factors underlying early placentopathy associated with intrauterine growth restriction caused by maternal alcohol consumption.

Combination of alcohol and glucose consumption as a risk to induce reactive hypoglycemia.

AIMS/INTRODUCTION: Alcohol consumption has been reported to cause hypoglycemia. However, the mechanism involved has not been unequivocally established. This study comprised healthy volunteers. We carried out a prospective trial to compare the effects of glucose and alcohol consumption, alone or in combination, on glucose and lipid metabolism. MATERIALS AND METHODS: A 75-g oral glucose tolerance test (OGTT), a combined 75-g glucose plus 20-g alcohol tolerance test (OGATT) and a 20-g alcohol tolerance test (OATT) were carried out in the participants. Plasma glucose, insulin, triglyceride and ethanol concentrations during each test were compared. RESULTS: We studied 10 participants. Their plasma glucose concentrations 15 and 30 min after the intake of 75 g of glucose were significantly higher during the OGATT than the OGTT. Hypoglycemia occurred in five participants after the OGATT, which was significantly more frequently than after the OGTT (P = 0.046). Hypoglycemia did not occur after the OATT, and the ethanol concentration was significantly lower after the OGATT than the OATT. The changes in triglyceride concentration from 30 min after the consumption of 75 g of glucose were significantly greater during the OGATT than the OGTT. The plasma insulin concentrations peaked after 60 min during both the OGTT and OGATT, and were significantly higher during the OGATT (P = 0.047). There were no differences between the two interventions in the Matsuda or disposition indexes. CONCLUSIONS: Hypoglycemia occurred more frequently after the simultaneous consumption of alcohol plus glucose than after the consumption of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia.

Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study.

INTRODUCTION: We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration. METHODS: This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reaction-time test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration. RESULTS: Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented. CONCLUSION: Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.

Characterization of motor function in mice developmentally exposed to ethanol using the Catwalk system: Comparison with the triple horizontal bar and rotarod tests.

Studies with human subjects indicate that ethanol exposure during fetal development causes long-lasting alterations in motor coordination that are, in part, a consequence of cerebellar damage. Studies with rats exposed to ethanol during the neonatal brain growth spurt have consistently recapitulated these deficits. However, studies with mice have yielded mixed results. We hypothesized that the use of highly sensitive motor function tests, such as the Catwalk test, would reliably detect motor function deficits in mice developmentally exposed to ethanol. Venus-vesicular GABA transporter transgenic mice were ethanol exposed during postnatal days 4-9 using vapor inhalation chambers and then subjected to the Catwalk test during adolescence. Catwalk data were rigorously analyzed using an innovative multistep statistical approach. For comparison, motor coordination and strength were assessed with the triple horizontal bar and rotarod tests. Unexpectedly, we found that out of 186 parameters analyzed in the Catwalk test, only one was affected by ethanol exposure (i.e., reduced coupling between left front paw and the right hind paw). In the triple horizontal bar test, ethanol-exposed mice were able to hold to the bars for less time than controls. Surprisingly, ethanol-exposed mice performed better in the rotarod test than controls. These data indicate that neonatal ethanol exposure of mice causes mixed effects on motor function during adolescence. The Catwalk test suggests that gait is generally preserved in these mice, whereas the triple horizontal bar test revealed deficits on motor strength and the rotarod test an increase in motor coordination.

Specialist alcohol inpatient treatment admissions and non-specialist hospital admissions for alcohol withdrawal in England: an inverse relationship.

AIMS: We assessed the relationship between specialist and non-specialist admissions for alcohol withdrawal since the introduction of the UK government Health and Social Care Act in 2012. METHODS: Using publicly available national data sets from 2009 to 2019, we compared the number of alcohol withdrawal admissions and estimated costs in specialist and non-specialist treatment settings. RESULTS: A significant negative correlation providing strong evidence of an association was observed between the fall in specialist and rise in non-specialist admissions. Significant cost reductions within specialist services were displaced to non-specialist settings. CONCLUSIONS: The shift in demand from specialist to non-specialist alcohol admissions due to policy changes in England should be reversed by specialist workforce investment to improve outcomes. In the meantime, non-specialist services and staff must be resourced and equipped to meet the complex needs of these service users.

Jacobian Mapping Reveals Converging Brain Substrates of Disruption and Repair in Response to Ethanol Exposure and Abstinence in 2 Strains of Rats.

BACKGROUND: In a previous study using Jacobian mapping to evaluate the morphological effects on the brain of binge (4-day) intragastric ethanol (EtOH) on wild-type Wistar rats, we reported reversible thalamic shrinkage and lateral ventricular enlargement, but persistent superior and inferior colliculi shrinkage in response to binge EtOH treatment. METHODS: Herein, we used similar voxel-based comparisons of Magnetic Resonance Images collected in EtOH-exposed relative to control animals to test the hypothesis that regardless of the intoxication protocol or the rat strain, the hippocampi, thalami, and colliculi would be affected. RESULTS: Two experiments [binge (4-day) intragastric EtOH in Fisher 344 rats and chronic (1-month) vaporized EtOH in Wistar rats] showed similarly affected brain regions including retrosplenial and cingulate cortices, dorsal hippocampi, central and ventroposterior thalami, superior and inferior colliculi, periaqueductal gray, and corpus callosum. While most of these regions showed significant recovery, volumes of the colliculi and periaqueductal gray continued to show response to each proximal EtOH exposure but at diminished levels with repeated cycles. CONCLUSIONS: Given the high metabolic rate of these enduringly affected regions, the current findings suggest that EtOH per se may affect cellular respiration leading to brain volume deficits. Further, responsivity greatly diminished likely reflecting neuroadaptation to repeated alcohol exposure. In summary, this unbiased, in vivo-based approach demonstrating convergent brain systems responsive to 2 EtOH exposure protocols in 2 rat strains highlights regions that warrant further investigation in both animal models of alcoholism and in humans with alcohol use disorder.

Taxifolin ameliorate high-fat-diet feeding plus acute ethanol binge-induced steatohepatitis through inhibiting inflammatory caspase-1-dependent pyroptosis.

Excessive alcohol drinking and a high-fat diet (HFD) promote steatohepatitis in the comorbidity of NAFLD and AFLD. Taxifolin (TAX) is a rich dihydroxyflavone compound found in onions, milk thistle and Douglas fir. We aimed to explore the intervention mechanism of TAX on chronic steatohepatitis induced by HFD feeding plus acute ethanol binge. We established an in vivo model by HFD feeding plus a single dose of ethanol binge, and established an in vitro model by oleic acid or palmitic acid on HepG2 cells to induce lipid accumulation. TAX regulated lipid synthesis by inhibiting the expression of SREBP1 and upregulating the PPARγ level. In addition, TAX inhibited the expression of P2X7R, IL-1ß, and caspase-1. Moreover, TAX reduced the expression of caspase-1 activation; thereby inhibiting the recruitment of macrophages and neutrophils. TAX also improved the inflammatory response caused by caspase-1 activation in steatotic hepatocytes. TAX exhibited an inhibitory effect on lipid accumulation and caspase-1-related pyroptosis. Collectively, TAX has therapeutic potential as an intervention of steatohepatitis induced by alcohol combined with HFD and for preventing non-alcoholic fatty liver degeneration targeting caspase-1-dependent pyroptosis.

Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms.

OBJECTIVE: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes. METHODS: A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings. RESULTS: Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial. CONCLUSIONS: The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.