Effect of ethanol and some alcoholic beverages on gastric emptying in humans

Background: There is a paucity of detailed and controlled studies on the action of ethanol and alcoholic beverages on gastric emptying in humans. This study was designed to compare the effect of beer, red wine, whisky and their comparable pure ethanol solutions on gastric emptying in a controlled and randomized investigation. Methods: On separate days, 10 healthy, fasted subjects received the following solutions, in random order, through a gastric tube: 500?mL beer, red wine, comparable pure ethanol solutions (4% and 10% v/v), glucose (5.5% and 11.4% w/v) and water, 125?mL whisky and 40% (v/v) ethanol (both followed by 125?mL water) and 250?mL water. Gastric emptying of the test solutions was assessed using ultrasonography of the antrum. Results: As measured by ultrasonography of the antrum, half emptying times of the ethanol solutions (4%, 10% and 40% v/v) were significantly (P?n?=?10) than those of water (14.6?±?1.9?min (500?mL) and 13.2?±?1.7?min (250?mL), respectively). The half emptying times of beer (39.3?±?4.3?min) and red wine (72.6?±?7.6?min) were significantly longer than those of the corresponding ethanol concentrations, whereas whisky was emptied at nearly the same rate (26.4?±?5.9?min) as 40% (v/v) ethanol. Emptying of glucose 5.5% and 11.4% (w/v) was significantly and dose dependently slower (29.7?±?4.5 and 64.8?±?8.9?min) than water. Conclusions: 1) Pure ethanol in concentrations of 4%, 10% and 40% (v/v) inhibits gastric emptying. 2) The inhibitory effect of beer and red wine, but not of whisky, is stronger than that of their comparable ethanol concentrations. 3) Caloric content and non‐alcoholic ingredients in alcoholic beverages produced by fermentation (beer and wine), but not in those produced by distillation (whisky), are most likely responsible for this effect.     

High-alcohol-content flavored alcoholic beverages (supersized alcopops) should be reclassified to reduce public health hazard

In the US, underage drinkers often consume supersized alcopop – a high-alcohol-content, ready-to-drink flavored alcoholic beverage that is currently regulated as beer. However, calculations in this paper illustrate how the high alcohol by volume and low price of supersized alcopops suggest that they rely on a larger proportion of additives for their alcohol content than permitted to meet the legal definition for beer. From a public safety perspective, it is urgently important that the Alcohol and Tobacco Tax and Trade Bureau assess the formulation of supersized alcopops – specifically, the percent of alcohol in the finished product that is derived from additives. Appropriate reclassification of supersized alcopops as distilled spirits would reduce youth access by resulting in increased price and reduced availability at the retail locations where youth most often obtain alcohol.     

Brand-specific consumption of flavored alcoholic beverages among underage youth in the United States

Background: Although several studies have identified flavored alcoholic beverages (FABs) as being popular among underage drinkers, no previous study has ascertained the prevalence of brand-specific FAB consumption among a national sample of underage youth. Objectives: To ascertain the brand-specific consumption prevalence and consumption share of FABs among a national sample of underage drinkers in the United States. Methods: In 2012, we conducted an online, self-administered survey of a national sample of 1031 underage drinkers, ages 13–20 years, to determine the prevalence of past 30-day consumption for each of 898 alcoholic beverage brands, including 62 FABs, and each brand's youth consumption share, based on the estimated total number of standard drinks consumed. There were three brand-specific outcome measures: prevalence of consumption, prevalence of consumption during heavy episodic drinking, and consumption share, defined as the percentage of the total drinks consumed by all respondents combined that was attributable to a particular brand. Results: The FAB brands with the highest prevalence of past 30-day consumption were Smirnoff malt beverages, 17.7%; Mike's, 10.8%; Bacardi malt beverages, 8.0%; and Four Loko/Four MaXed, 6.1%. Just five brands accounted for almost half (49.1%) of the total consumption share by volume within the FAB category. Conclusion: Flavored alcoholic beverages are highly popular among underage drinkers, and the FAB brand preferences of this group are highly concentrated among a small number of brands. To decrease the consumption of FABs by underage youth, all states should reclassify these beverages as distilled spirits rather than beer.     

Role of acetaldehyde in the discriminative stimulus effects of ethanol

BACKGROUND: Acetaldehyde has been suggested to mediate some of the effects of ethanol. Acetaldehyde can be produced by the enzyme catalase within the brain after ethanol administration. The catalase inhibitor 3-amino-1,2,4-triazole (AT) reduces the production of acetaldehyde, and AT administration can reduce a number of ethanol-induced behavioral effects; this suggests the involvement of acetaldehyde in these behaviors. However, a role for acetaldehyde in mediating the discriminative stimulus effects of ethanol remains unclear. METHODS: The contribution of acetaldehyde to the discriminative stimulus effects of ethanol was investigated by use of a two-lever drug discrimination paradigm with food reinforcement. Male Long-Evans rats were trained to discriminate water from either 1.0 or 2.0 g/kg ethanol. Stimulus substitution tests were conducted with ethanol (0-2.5 g/kg by gavage) and acetaldehyde (0-300 mg/kg intraperitoneally). A cumulative dose-response procedure was then used to investigate the effects of pretreatments with AT (0.5 and 1.0 g/kg intraperitoneally) on ethanol discrimination. RESULTS: Acetaldehyde up to doses that decreased response rates (300 mg/kg) did not substitute for the discriminative stimulus effects of 1.0 or 2.0 g/kg ethanol. In addition, AT pretreatment did not affect the dose-response curves for ethanol discrimination. CONCLUSIONS: These results show that exogenous acetaldehyde administration does not produce discriminative stimulus effects that are similar to those of ethanol. Also, pretreatment with the catalase inhibitor did not affect the dose-response curve for ethanol discrimination, and this suggests that endogenously produced acetaldehyde does not contribute to the discriminative stimulus effects of ethanol. Together these results suggest that acetaldehyde does not mediate the discriminative stimulus effects of 1.0 to 2.0 g/kg ethanol.     

Increase in the incidence of alcoholic pancreatitis and alcoholic liver disease in Iceland: impact of per capita alcohol consumption

Abstract

Objective: To analyze the incidence of acute alcoholic pancreatitis and of severe alcoholic liver disease (ALD) and its association with per capita alcohol consumption with identification of both alcoholic cirrhosis (AC) and severe alcoholic hepatitis (AH), in a population-based setting.

Methods: A search was undertaken in diagnoses database for diagnostic codes in order to find patients hospitalized with incident acute alcoholic pancreatitis (AP) and alcoholic liver disease in Iceland in 2001–2015. Diagnoses were verified in all patients who were retrospectively reviewed. Those with ALD had either AC or AH. Alcohol sales during the study period were obtained from Statistics Iceland.

Results: Overall, 273 patients with acute AP, mean age at diagnosis 50 (14) years, 74% males and 159 patients with ALD, mean age 57 (11) years, 73% males, were identified. Mean per capita alcohol consumption was 6.95 (0.4) liters and increased by 21% over the study period. The annual incidence of AP increased from 4.2 per 100.000 to 9.5 and ALD from 1.6 to 6.1 per 100.000. Trend analysis showed a significant annual increase of 7% (RR 1.07, 95%CI 1.04–1.10) for AP and an annual increase of 10.5% (RR 1.10, 95%CI 1.06–1.15) for ALD. The increase was only significant in males.

Conclusions: Increase per capita alcohol consumption over a 15?year study period was associated with an increase in the incidence of severe alcoholic liver disease and alcohol-related acute pancreatitis in males but not in females.     

The Nature and Extent of Flavored Alcoholic Beverage Consumption among Underage Youth: Results of a National Brand-Specific Survey

Background: Flavored alcoholic beverages are popular among underage drinkers. Existing studies that assessed flavored alcoholic beverage use among youth relied upon respondents to correctly classify the beverages they consume, without defining what alcohol brands belong to this category. Objectives: The aim is to demonstrate a new method for analyzing the consumption of flavored alcoholic beverages among youth on a brand-specific basis, without relying upon youth to correctly classify brands they consume. Methods: Using a prerecruited Internet panel developed by Knowledge Networks, we measured the brands of alcohol consumed by a national sample of youth drinkers, aged 16–20 years, in the United States. The sample consisted of 108 youths who had consumed at least one drink of an alcoholic beverage in the past 30 days. We measured the brand-specific consumption of alcoholic beverages within the past 30 days, ascertaining the consumption of 380 alcohol brands, including 14 brands of flavored alcoholic beverages. Results: Measuring the brand-specific consumption of flavored alcoholic beverages was feasible. Based on a brand-specific identification of flavored alcoholic beverages, nearly half of the youth drinkers in the sample reported having consumed such beverages in the past 30 days. Flavored alcoholic beverage preference was concentrated among the top four brands, which accounted for almost all of the consumption volume reported in our study. Conclusions and scientific significance: These findings underscore the need to assess youth alcohol consumption at the brand level and the potential value of such data in better understanding underage youth drinking behavior and the factors that influence it.     

First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying

Background—Ethanol undergoes a first passmetabolism (FPM) in the stomach and liver. Gastric FPM of ethanolprimarily depends on the activity of gastric alcohol dehydrogenase(ADH). In addition, the speed of gastric emptying (GE) may modulateboth gastric and hepatic FPM of ethanol.
Aims—To study the effect of modulation of GE onFPM of ethanol in the stomach and liver.
Methods—Sixteen volunteers (eight men andeight women) received ethanol (0.225 g/kg body weight) orally andintravenously, and the areas under the ethanol concentration timecurves were determined to calculate FPM of ethanol. In seven of thesesubjects, FPM of ethanol was measured after the intravenousadministration of 10 mg metoclopramide (MCP) and 20 mgN-butylscopolamine (NBS) in separate experiments to eitheraccelerate or delay GE. GE was monitored sonographically by integrationof the antral area of the stomach every five minutes for 90 minutesafter oral ethanol intake. In addition, gastric biopsy specimens weretaken to determine ADH activity and phenotype, as well as to evaluategastric histology. Blood was also drawn for ADH genotyping.
Results—GE time was significantly delayed by theadministration of NBS as compared with controls (p<0.0001) and ascompared with the administration of MCP (p<0.0001). This wasassociated with a significantly enhanced FPM of ethanol with NBScompared with MCP (p = 0.0004). A significant correlation was notedbetween GE time and FPM of ethanol (r = 0.43, p = 0.0407).Gastric ADH activity did not significantly correlate with FPM of ethanol.
Conclusion—FPM of ethanol is strikingly modulatedby the speed of GE. Delayed GE increases the time of exposure ofethanol to gastric ADH and may therefore increase gastric FPM ofethanol. In addition, hepatic FPM of ethanol may also be enhanced asthe result of slower absorption of ethanol from the small intestine. Thus a knowledge of GE time is a major prerequisite for studying FPM ofethanol in humans.

Keywords:first pass metabolism of ethanol; gastric emptying; alcohol dehydrogenase; ethanol metabolism; stomach

     

Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. I: Studies in outbred animals

BACKGROUND: This study was designed to investigate the relationship between the ethanol-oxidizing capacity of the brain, accumulation of acetaldehyde, and ethanol-induced hypnosis in animals in vivo. METHODS: Randomly outbred albino rats were treated with ethanol, and the duration of ethanol-induced loss of the righting response (sleep time) was measured. They were killed 2 weeks later (without further in vivo administration of ethanol), and brain homogenates were prepared to measure the accumulation of acetaldehyde from ethanol added in vitro. In a similar way, we determined the sleep time and, 5 days later, the rates of acetaldehyde accumulation in brains of heterogeneous mice. RESULTS: Significant correlations between the duration of ethanol-induced sleep and acetaldehyde accumulation in vitro were found. The Km value of the process of acetaldehyde accumulation was lower in long-sleeping, as compared with short-sleeping, rats. A similar result was also obtained in genetically heterogeneous mice. Animals with a longer duration of ethanol-induced sleep had a higher level of the accumulation of ethanol-derived acetaldehyde in brain homogenates, as compared with the short-sleeping mice. Rats and mice with the intermediate duration of ethanol-induced sleep had an intermediate value of acetaldehyde accumulation in brain homogenates. There was no correlation between brain catalase activity and ethanol-induced loss of the righting response in either the rats or the mice. CONCLUSIONS: This study is a direct demonstration of the positive correlation between ethanol-derived acetaldehyde accumulation in vitro in the brain and a central (behavioral) effect of alcohol in outbred rats and mice in vivo.     

Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells

BACKGROUND: Alcoholism is a common cause of cirrhosis. Hepatic stellate cells are the main source of collagen that ultimately leads to hepatic fibrosis and cirrhosis. Reactive oxygen species (ROS) enhance stellate cell activation and stimulate fibrogenesis. In this study, the acute effects of ethanol (ET) and acetaldehyde (AC) were determined on the production of ROS in isolated rat hepatic stellate cells. METHODS: Rat stellate cells were isolated in situ by perfusion of the portal vein and cultured. Hydrogen peroxide (H(2)O(2)) was determined by luminol-derived chemiluminescence (CL), while superoxide anion (O(2*-)) production was assessed by the fluorescent probe hydroethidine. RESULTS: AC increased the formation of H(2)O(2) and O(2*-), and these effects were first detectable at AC concentrations of 5 and 10 microM, respectively, reaching a maximum at 50 to 75 microM. Reduction of glutathione (GSH) synthesis by 1-buthionine sulfoximide (BSO) or by GSH conjugation with dimethylmaleate (DEM) further enhanced the effects of AC on H(2)O(2) and O(2*-) formation, while N-acetylcysteine (NAC) decreased H(2)O(2) and eliminated the enhanced generation of O(2*-) caused by AC. Raloxifene, which inhibits O(2*-) production by NAD(P)H oxidase, reduced the effects of AC on H(2)O(2) and O(2*-) production. ET increased H(2)O(2) or O(2*-) only in the presence of BSO or DEM. CONCLUSION: This study shows that concentrations of AC, which occur in vivo after the ingestion of alcoholic beverages, result in the formation of ROS in rat hepatic stellate cells. The increases in ROS are known to activate stellate cells promoting fibrogenesis.     

Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat

Background: Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), is produced peripherally by gastric and hepatic alcohol dehydrogenase (ADH) and centrally by brain catalase. In spite of the aversive properties classically ascribed to ACD, it has recently been suggested that ACD might mediate some of the motivational effects of EtOH. Accordingly, the relative role of ACD in the positive motivational properties of EtOH ingested is increasingly becoming the matter of debate. Thus, we studied the ability of intragastrically administered EtOH, ACD and EtOH‐derived ACD to induce conditioned place preference (cpp) in rats. Methods: Wistar rats were pretreated intraperitoneally with saline, the peripheral competitive inhibitor of ADH, 4‐methylpyrazole (4‐MP, 22.5, 45 or 67.5 mg/kg) or with the selective ACD‐sequestrating agent, d ‐penicillamine (DP, 25 or 50 mg/kg), before the intragastric administration of saline, EtOH (0.5, 1 or 2 g/kg) or ACD (10, 20, or 40 mg/kg). The specificity of 4‐MP and DP effects was addressed using morphine‐induced cpp (2.5 mg/kg). Results: Both, EtOH and ACD dose‐dependently induced cpp; further, while EtOH‐induced cpp was prevented by the administration of 4‐MP and by DP, ACD‐induced cpp was unaltered by 4‐MP administration and prevented by DP. Both pretreatments did not interfere with morphine‐induced cpp indicating that 4‐MP and DP specifically modulate the motivational properties of EtOH and ACD. Conclusion: The ability of 4‐MP and DP to decrease EtOH‐induced cpp suggests that a reduction of ACD levels is crucial in depriving EtOH from its motivational properties as indexed by the cpp procedure. In addition, this conclusion is supported by the inefficacy of 4‐MP in preventing ACD‐induced cpp, and by its blockade observed after administration of the selective ACD sequestrating agent DP. The present results underscore the role of EtOH‐derived ACD in EtOH‐induced motivational properties as well as its abuse liability.     

Sugar sweetened beverages consumption and risk of coronary heart disease: A meta-analysis of prospective studies

Objective

To summarize the evidence with respect to sugar sweetened beverages (SSBs) consumption and risk of coronary heart disease (CHD) and to recommend field standards for future analysis on this topic.

Methods

We searched for articles published up to February 2013 through PubMed, EMbase, and Cochrane Library Database and reviewed reference list of the retrieved articles. Prospective studies with reported relative risks (RRs) with 95% confidence intervals (CIs) of CHD for different categories of SSBs consumption were included. Random-effects models were used to evaluate the associations by comparing the highest and lowest categories of SSBs consumption in relation to risk of CHD.

Results

Four prospective studies with 7396 CHD cases among 173,753 participants were included in the meta-analysis. The pooled RR (95% CI) for CHD in the highest category of SSBs consumption in comparison with the lowest category of SSBs was 1.17 (1.07–1.28). Stratified analyses indicated a significant association for men but not for women, with pooled RRs (95%CI) of 1.17 (1.05–1.29) and 1.19 (0.94–1.50), respectively. For studies carried out in America, the pooled RR for CHD was 1.18 (1.07–1.30). Additionally, a one-severing per day increase in SSBs consumption was associated with a 16% increased risk of CHD (RR: 1.16, 95%CI: 1.10–1.23).

Conclusion

Our meta-analysis of four studies suggests that consumption of SSBs may increase risk of CHD, especially among men and American populations. However, this finding was based on limited studies; further studies are warranted to critically evaluate the relationship.     

Polymorphisms in the transforming growth factor-beta gene (TGF-beta) and the risk of advanced alcoholic liver disease.

BACKGROUND/AIMS: There are wide interindividual differences in the risk of developing alcoholic cirrhosis. Transforming growth factor beta(1) (TGF-beta(1)) is the main cytokine involved in liver fibrogenesis. The TGF-beta(1) gene is polymorphic at several sites and these polymorphisms are probably related to differences in the rate of TGF-beta(1) synthesis. Our aim has been to analyse the influence of the TGF-beta(1) gene polymorphisms in the predisposition to advanced alcoholic liver disease (ALD) in ethanol abusers. METHODS: TGF-beta(1) single nucleotide polymorphisms at positions -509 (C or T), +869 (C or T, codon 10), and +915 (C or G, codon 25) were examined in 165 alcoholics with advanced ALD and in 185 healthy controls. RESULTS: Among the 94 male patients with oesophageal varices, those carrying the GG genotype at position +915 were diagnosed at an older age than the remaining patients (age 52.1 years, standard deviation (SD) 9.9 vs. 45 SD 13.4, P=0.012). No other statistically significant differences were found in the distribution of the three TGF-beta(1) polymorphisms analysed individually or as combined haplotypes. CONCLUSIONS: The polymorphisms at the TGF-beta(1) gene analysed in this study are probably not related to the risk of advanced ALD.     

Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects--a commentary

Background: This commentary discusses a study by Karahanian and colleagues (2011) on the role of central nervous system acetaldehyde in the reinforcing effects of ethanol. The goal is to emphasize the importance of the study and to discuss future directions. Results: This important paper solidifies the idea that the levels of acetaldehyde in the central nervous system have profound effects in mediating the reinforcing actions of ethanol. This is accomplished by manipulating the brain levels of acetaldehyde produced from ethanol by the injection of lentivirus containing either an anti‐catalase shRNA construct or a rat liver alcohol dehydrogenase into the central nervous system and observing the effects on alcohol preference by high ethanol‐consuming rats. A factor not directly considered is that acetaldehyde is further metabolized to acetate, which also has some behavioral actions. Conclusions: The efficacy of lentivirus injections of enzyme inhibitors or enzymes themselves to alter a behavioral response to ethanol is clearly demonstrated here. The many other actions of ethanol that are postulated to be a result of the production of acetaldehyde in the brain remain to be investigated by similar techniques. Possible “therapeutic avenues to reduce chronic alcohol use” are envisioned.     

Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects

Background: While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis. Methods: The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar‐derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results: Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (?94%p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption. Conclusions: The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.     

Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. II: Studies in selectively bred rats and mice

BACKGROUND: To clarify the role of brain acetaldehyde in the hypnotic effect of ethanol, we compared the ethanol-oxidizing capacity (rate of acetaldehyde accumulation) and catalase and aldehyde dehydrogenase activity in the brains of animals genetically selected for different sensitivities to the hypnotic effect of ethanol. METHODS: We used high, low, or control alcohol-sensitive rats (HAS, LAS, and CAS) and short- and long-sleep mice (SS and LS), as well as SS x LS recombinant inbred mice with known strain differences in mean duration of ethanol-induced sleep. We studied the rate of accumulation of acetaldehyde from ethanol in brain homogenates of these animals and correlated those values with their hypnotic sensitivity to ethanol. RESULTS: Acetaldehyde accumulation from ethanol was significantly higher in the brain homogenates from HAS rats and LS mice with high sensitivity to the hypnotic effect of ethanol in vivo, compared with LAS rats and SS mice with low sensitivity to ethanol. A correlation was found between the duration of ethanol-induced sleep and the in vitro rate of accumulation of ethanol-derived acetaldehyde in the brains of recombinant SS x LS mice strains. There was no correlation of sleep time with brain catalase levels. There were no line differences in brain catalase or aldehyde dehydrogenase or in alcohol or aldehyde dehydrogenase activity in livers of LAS, CAS, and HAS rats or in SS and LS mice. CONCLUSIONS: A correlation between the brain acetaldehyde accumulation, but not catalase levels, and the central effect of ethanol was demonstrated in animals genetically differing in initial sensitivity to the hypnotic effect of ethanol.