bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metronidazole Increases Intracolonic but Not Peripheral Blood Acetaldehyde in Chronic Ethanol‐Treated Rats
Authors: Tillonen Jyrki , Väkeväinen Satu , Salaspuro Ville , Zhang Yong , Rautio Merja , Jousimies‐Somer Hannele , Lindros Kai , Salaspuro Mikko 
Published: April 2006

Background: Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram‐like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long‐term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram‐like reaction.Methods: A total of 32 rats were divided into four groups: controls (n= 6), controls receiving metronidazole (n= 6), ethanol group (n= 10), and ethanol and metronidazole group (n= 10). All rats were pair‐fed with the liquid diet for 6‐weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed.Results: The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 ± 163.5 μM vs. 84.7 ± 14.4 μM, p= 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities.Conclusions: The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH‐containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram‐like reaction might be located in the gut flora instead of the liver.
Changes in Microsomal Activity in Alcoholism and Obesity
Authors: de la Maza M. Pía , Hirsch Sandra , Petermann Margarita , Suazo Myriam , Ugarte Guillermo , Bunout Daniel 
Published: April 2006

Background: Liver damage is more prevalent among obese alcoholics, and cytochrome P‐450–2E1(CYP2E1) induction is involved in its pathogenesis.Objectives The study was undertaken to assess microsomal function, in alcoholic and nonalcoholic male subjects with different body compositions, through pharmacokinetics of chlorzoxazone (CLZ). We also intended to study the relationship between CLZ hydroxylation and urinary levels of 8‐hydroxydiguanosine, and between CLZ levels and liver histology.Methods: Serial measurements of CLZ serum concentration, after a 750 mg dose, were performed in 17 alcoholics (9 normal weight and 8 obese) and 21 nonalcoholic subjects (10 normal weight and 11 obese). Concentration of 6‐hydroxy‐chlorzoxazone (6‐OH‐CLZ) was determined at the second hour. Anthropometry, clinical laboratory tests, and urinary 8‐hydroxydiguanosine concentrations were measured. Liver biopsies were performed in alcoholics.Results: Five biopsies revealed severe lesions, one in normal‐weight and four in obese patients (p= NS). Area under the curve (AUC) of CLZ was higher in normal‐weight controls compared with the rest of the groups (ANOVA p= 0.001). This parameter correlated negatively with adiposity in nonalcoholic subjects and did not correlate with liver histology. 6‐OH‐CLZ/CLZ ratio was lower in normal‐weight controls, compared with obese subjects and normal‐weight alcoholics (p= 0.02). Both alcoholism and obesity were included as predictors of CLZ AUC in a multiple regression analysis. The two‐factor ANOVA showed an additive effect of centripetal body fat distribution and alcoholism. Urinary 8‐hydroxydiguanosine levels were extremely variable.Conclusions: Centripetal adiposity and alcoholism are associated with induction of CYP2E1. This may explain the higher prevalence of liver damage among obese alcoholics and also nonalcoholic steatohepatitis.
An Examination of the Synergistic Interaction of Ethanol and Thiamine Deficiency in the Development of Neurological Signs and Long‐Term Cognitive and Memory Impairments
Authors: Ciccia Rosanne M. , Langlais Philip J. 
Published: April 2006

Background: The prolonged and heavy consumption of ethanol has been associated with thiamine deficiency and a wide range of cognitive and memory impairments. The present study was undertaken to test the hypothesis that ethanol and thiamine deficiency act synergistically, producing more severe clinical neurological disturbances and cognitive and memory impairments than either thiamine deficiency or chronic ethanol alone.Methods: The acute neurological and long‐term behavioral consequences of combined chronic (32 weeks) ethanol consumption (20% v/v in drinking water) and three separate 4‐week long episodes of dietary thiamine deficiency (ET/TD) versus ethanol (ET) or thiamine deficiency (TD) treatments alone were examined in male Sprague Dawley® rats aged 12 weeks at the start of treatment.Results: The ET/TD group lost less weight than the TD group during each episode of thiamine deficiency. Contrary to expectations, the progression and severity of ataxia, impaired righting reflexes, and opisthotonic posturing were similar in the ET/TD and TD groups. None of the ET animals displayed any neurological or behavioral symptoms during treatment. After withdrawal from ethanol and a 7‐week recovery period, none of the groups differed in spontaneous activity. On subsequent testing, the ET group displayed a significant increase in perseverative responding in a spontaneous alternation task. A small but significant proportion of ET/TD (23%), ET (17%), and TD (8%) animals were unable to reach criterion on an initial nonmatching‐to‐position task (NMTP) or in two subsequent reversals of the matching and NMTP tasks, which indicated persistent learning impairments. A large proportion of animals in each of the three groups demonstrated significantly reduced accuracy compared with controls at longer delays of matching‐to‐position tasks (MTP), but only the ET group was consistently impaired at the shorter delays. There were no significant correlations between blood ethanol concentration and any of the learning and memory measures.Conclusions: These results indicate that the interaction of chronic ethanol consumption and bouts of TD is both domain specific and not always synergistic. Learning and reference memory appear to be sensitive to a synergistic interaction of ET and TD, whereas short‐term working memory disturbances are most affected by ET and neurological symptoms are most associated with TD. Furthermore, neither the presence of neurological symptoms nor blood ethanol concentrations appear to be good predictors of learning and memory deficits.
Pharmacological Treatments for Alcoholism: Revisiting Lithium and Considering Buspirone
Authors: Fawcett Jan , Kravitz Howard M. , McGuire Marcella , Easton Michael , Ross Jeffrey , Pisani Vincent , Fogg Louis F. , Clark David , Whitney Michael , Kravitz Glenda , Javaid Javaid , Teas Gregory 
Published: April 2006

Objective Previous research has suggested that both lithium and buspirone could lessen alcoholics’ desire to drink as well as reduce the actual amounts of alcohol consumed. The purpose of this study was to compare lithium and buspirone monotherapy with placebo on outcomes of abstinence, alcohol quantity consumed, treatment retention and compliance, and medication side effects.Methods: We conducted a randomized, double‐blind, placebo‐controlled, three‐arm parallel group, clinical trial that compared lithium and buspirone with placebo in 156 alcohol‐dependent men.Results: Study retention rates for the three treatment groups at 3 and 6 months, respectively, were 61% and 46% for lithium, 44% and 27% for buspirone, and 52% and 38% for placebo (p= NS, for 3 and 6 months). Overall abstinence rates were 28% and 19% at 3 and 6 months, respectively. However, mean daily quantities of alcohol consumed and percentage of drinking days decreased significantly (p < 0.0001) over time in all treatment groups. Differential improvement was seen only for the decrement in quantity consumed in the buspirone group, compared with the placebo group, but only at a trend level (p= 0.07). According to pill counts, compliance did not differ significantly among the treatment groups.Conclusions: These results do not support the hypothesis that either lithium or buspirone, compared with placebo, produces differential reductions in alcohol consumption. The results suggest the need to enhance treatment retention to maximize outcomes.
Partial Rescue of Ethanol‐Induced Neuronal Apoptosis by Growth Factor Activation of Phosphoinositol‐3‐Kinase
Authors: de la Monte Suzanne M. , Ganju Neema , Banerjee Kakoli , Brown Nancy V. , Luong Tri , Wands Jack R. 
Published: April 2006

Background: Ethanol inhibition of insulin signaling pathways may contribute to impaired central nervous system (CNS) development in the fetal alcohol syndrome and brain atrophy associated with alcoholic neurodegeneration. Previous studies demonstrated ethanol inhibition of insulin‐stimulated growth in PNET2 CNS‐derived proliferative (immature) neuronal cells. We now provide evidence that the growth‐inhibitory effect of ethanol in insulin‐stimulated PNET2 cells is partly due to apoptosis.Methods: Control and ethanol‐treated PNET2 cells were stimulated with insulin and analyzed for viability, apoptosis, activation of pro‐apoptosis and survival gene expression and signaling pathways, and evidence of caspase activation.Results: Ethanol‐treated PNET2 neuronal cells exhibited increased apoptosis mediated by increased levels of p53 and phospho‐amino‐terminal c‐jun kinase (phospho‐JNK), and reduced levels of Bcl‐2, phosphoinositol 3‐kinase (PI3 K), and intact (∼116 kD) poly (ADP ribose) polymerase (PARP), a deoxyribonucleic acid repair enzyme and important substrate for caspase 3. Partial rescue from ethanol‐induced neuronal cell death was effected by culturing the cells in medium that contained 2% fetal calf serum instead of insulin, or insulin plus either insulin‐like growth factor type 1 or nerve growth factor. The resulting enhanced viability was associated with reduced levels of p53 and phospho‐JNK and increased levels of PI3 K and intact PARP.Conclusions: The findings suggest that ethanol‐induced apoptosis of insulin‐stimulated neuronal cells can be reduced by activating PI3 K and inhibiting pro‐apoptosis gene expression and intracellular signaling through non‐insulin‐dependent pathways.
Ethanol‐Induced Up‐Regulation of Candidate Plasminogen Receptor Annexin II in Cultured Human Endothelial Cells
Authors: Tabengwa Edlue M. , Abou‐Agag Laila H. , Benza Raymond L. , Torres Jose A. , Aikens Michael L. , Booyse Francois M. 
Published: April 2006

Introduction Epidemiological studies indicate that moderate alcohol consumption reduces the risk for coronary heart disease and that this cardioprotective benefit may be mediated, in part, by increased fibrinolysis. Endothelial cells (ECs) synthesize plasminogen activators, tissue‐type plasminogen activator (t‐PA), urokinase‐type plasminogen activator (u‐PA), receptors for plasminogen activators, and a receptor for plasminogen, annexin II (Ann‐II). These receptors localize and facilitate receptor‐bound plasminogen activator‐mediated conversion of receptor‐bound plasminogen to receptor‐bound plasmin on the EC surface, which results in the regulated expression of surface‐localized EC fibrinolytic activity. Ethanol is a systemic factor that affects these components, which increases EC fibrinolysis and hence reduces the risk for thrombosis, coronary heart disease, and myocardial infarction (MI).Methods: This study was carried out to determine whether low ethanol (0.1% v/v) increased plasminogen receptor, Ann‐II antigen (western blot), messenger ribonucleic acid (mRNA) (reverse transcription polymerase chain reaction; RT‐PCR) expression, activity (ligand binding/Scatchard analysis), and hence fibrinolysis (plasmin generation) in cultured human ECs.Results: Plasminogen receptor activity increased ∼2‐fold (2.5 vs. 5.6 × 106 sites/cell), as evidenced by increased 125I‐labeled Glu‐plasminogen ligand binding/Scatchard analysis. In addition, western blot analyses indicated an increase in Ann‐II antigen, and mRNA levels increased ∼2‐fold (RT‐PCR). This increase in Ann‐II expression was concomitant with ∼2‐ to 3‐fold sustained increase (∼24 hr) in surface‐localized EC fibrinolytic activity. Nuclear transcription run‐on assays showed an ∼5‐ to 6‐fold increase in new 32P‐labeled Ann‐II mRNA levels, compared with controls (no ethanol).Conclusions: These results demonstrated that low ethanol increased Ann‐II antigen/mRNA levels and up‐regulated Ann‐II gene expression at the transcriptional level. The results further identify and define the contribution and role of the plasminogen receptor, Ann‐II, in the ethanol‐induced mechanism of increased EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
Dissociation Between the Time Course of Ethanol and Extracellular Dopamine Concentrations in the Nucleus Accumbens After a Single Intraperitoneal Injection
Authors: Yim Hyeon Joo , Robinson Donita L. , White Martha L. , Jaworski Jason N. , Randall Patrick K. , Lancaster Francine E. , Gonzales Rueben A. 
Published: April 2006

Background: Dopamine release in the nucleus accumbens has been linked to the reinforcing effects of ethanol, but the time course or relationship of this response to ethanol concentrations in the brain has not been studied.Methods: Various doses of ethanol (0–2.0 g/kg) were administered intraperitoneally to male Sprague Dawley® rats, and dopamine and ethanol were simultaneously analyzed in dialysate samples from the nucleus accumbens. A separate study to compare the ethanol‐induced dopamine response in male and female rats was carried out by using a 1 g/kg intraperitoneal dose of ethanol.Results: In male rats, 1 and 2 g/kg ethanol significantly increased dialysate dopamine by 40% over basal, whereas 0.25 and 0.5 g/kg ethanol produced a nonsignificant 20% increase. Dialysate ethanol concentrations exhibited a curvilinear decline after reaching peak levels for the lower doses but showed a linear decrease after 1 and 2 g/kg. There was a dissociation between the time courses of extracellular dopamine and ethanol after 1 and 2 g/kg ethanol treatment. The dopamine response returned to basal within 90 min, whereas the ethanol concentrations remained elevated. In a separate study that compared male and female rats, the ratio of the dopamine response over basal to the dialysate ethanol concentrations was significantly decreased at 60 min after an injection of 1 g/kg. However, there were no differences between males and females.Conclusions: The dissociation between dopamine and ethanol levels may reflect the development of acute tolerance to ethanol‐induced dopamine release in the nucleus accumbens within the time course of a single acute injection. Given the strong links between dopamine and ethanol reinforcement, our findings may be relevant for understanding the time course of ethanol's reinforcing effects in vivo.
Regional Brain Metabolism During Alcohol Intoxication
Authors: Wang Gene‐Jack , Volkow Nora D. , Franceschi Dinko , Fowler Joanna S , Thanos Panayotis K. , Scherbaum Nobert , Pappas Naomi , Wong Christopher T. , Hitzemann Robert J. , Felder Christoph A. 
Published: April 2006

Background: Ethanol has a broad range of actions on many neurotransmitter systems. The depressant actions of ethanol in the brain are related in part to facilitation of γ‐aminobutyric acid (GABA) neurotransmission via its interaction with the benzodiazepine/GABA receptor complex. The purpose of this study was to evaluate the effects of ethanol on regional brain metabolism in 10 healthy right‐handed men. The results were compared with those we previously published in a different group of 16 normal male subjects who received intravenous lorazepam, a benzodiazepine drug that also enhances GABA neutrotranmission.Methods: The subjects were scanned with positron emission tomography and [F‐18] fluorodeoxyglucose twice: 40 min after the end of placebo (diet soda) or ethanol (0.75 g/kg) oral administration. Image data sets were analyzed by using both the region of interest and the statistical parametric mapping (SPM) approach. SPM was used to generate a difference image between baseline and ethanol, which we compared to the difference image between baseline and lorazepam (30 μg/kg).Results: Ethanol significantly increased self‐reports of “high” (p≤ 0.0001), dizziness (p≤ 0.004), and intoxication (p≤ 0.0001). Ethanol significantly decreased whole brain (−25 ± 6%, p≤ 0.0001) and regional metabolism. Normalization of the regional measures by whole brain metabolism (relative measures) showed that ethanol decreased relative metabolic activity in occipital cortex (−4.9 ± 4.1%, p≤ 0.006), whereas it increased relative metabolic act in left temporal cortex (+3.5 ± 2.9%, p≤ 0.006) and left basal ganglia (+9 ± 6.3%, p≤ 0.0009). SPM analyses revealed the same pattern of responses as the relative measures, showing decreases in occipital cortex and increases in left temporal cortex. Comparison of the relative measures and the SPM analyses obtained with lorazepam data revealed a similar pattern of effects, with relative decreases in occipital cortex (−7.8 ± 4.8%) and relative increases in left temporal cortex (+3.8 ± 5.7%). Lorazepam, but not ethanol, also decreased thalamic metabolism (−11.2 ± 7.2%).Conclusions: These results support similar though not identical mechanisms for the effects of alcohol and benzodiazepines on brain glucose metabolism. The fact that lorazepam, but not alcohol, reduced thalamic metabolism, an effect associated with sleepiness, could explain the higher sedative effects of lorazepam than of alcohol.
High Salivary Acetaldehyde After a Moderate Dose of Alcohol in ALDH2‐Deficient Subjects: Strong Evidence for the Local Carcinogenic Action of Acetaldehyde
Authors: Väkeväinen Satu , Tillonen Jyrki , Agarwal Dharam P. , Srivastava Nidhi , Salaspuro Mikko 
Published: April 2006

Background: Due to a point mutation, aldehyde dehydrogenase‐2 (ALDH2) isoenzyme is deficient in 30% to 50% of Asians. Among Asian ALDH2‐deficient heavy drinkers, the risk for digestive tract cancers is markedly increased (odds ratio 3.4–54.2). The reason for this is unknown but could be due to the local carcinogenic action of acetaldehyde.Methods: Salivary and blood acetaldehyde levels were determined in 20 healthy Asians after a moderate dose of alcohol (0.5 g/kg of body weight). Salivary acetaldehyde production capacity from ethanol in vitro was measured also. ALDH2 genotype of the Asians was determined from isolated leukocyte‐deoxyribonucleic acid by polymerase chain reaction/restriction fragment length polymorphism method. Acetaldehyde content of parotid gland saliva was measured in three ALDH2‐deficient Asians and three White subjects with normal ALDH2 after the same dose of ethanol.Results: Seven of the Asians were heterozygous for the mutant ALDH2*2 allele (flushers). They had two to three times higher salivary acetaldehyde levels than the Asians (n= 13) with normal ALDH2 throughout the follow‐up period of 240 min (p < 0.001). Only in the flushers did the parotid gland contribute to salivary acetaldehyde production. The in vitro capacity of saliva to produce acetaldehyde from ethanol was equal in both groups. The flushers’ blood acetaldehyde levels were only one ninth of the levels in saliva.Conclusions: By using this human “knockout model” for deficient acetaldehyde removal, we found that in addition to oral microflora, acetaldehyde in saliva may also originate from the oxidation of ethanol in the parotid gland. When combined with earlier epidemiological data, these results offer a strong evidence for the local carcinogenic action of acetaldehyde in humans.
Trajectories of Concurrent Substance Use Disorders: A Developmental, Typological Approach to Comorbidity
Authors: Jackson Kristina M. , Sher Kenneth J. , Wood Phillip K. 
Published: April 2006

Background: Although alcohol and tobacco use disorders are highly comorbid, little is known regarding the combined course of these disorders.Methods: The current study utilized latent class analysis to examine longitudinal patterns of alcohol–tobacco use disorder comorbidity. Participants were 449 young adults (baseline age, 18.5 years; 48% male; 51% with paternal history of alcoholism) assessed five times over 7 years.Results: Five longitudinal types of alcohol or tobacco use disorder over time were identified: nondiagnosing; developmentally limited alcohol use disorder; chronic alcohol use disorder; chronic tobacco use disorder; and comorbid alcohol and tobacco use disorder. These typologies were distinguishable on the basis of family history of alcoholism status and sex. Etiologically important third variables (alcohol expectancies, behavioral undercontrol, childhood stressors) mediated the relation between family history and the latent classes.Conclusions: Characterizations of alcohol use disorders typically fail to consider important sources of heterogeneity such as course or comorbidity. By simultaneously modeling developmental course and comorbidity with tobacco dependence, we were able to identify distinct trajectories of single and concurrent substance use disorders. Such multi‐substance trajectories represent meaningful subtypes that, although sharing substantial common influences, have unique etiologic correlates. Additionally, these subtypes might represent distinct groups from the perspective of intervention strategies.