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CORK Bibliography: Neonatal Abstinence Syndrome

54 citations. January 2007 to present

Prepared: March 2010

Agthe AG; Kim GR; Mathias KB; Hendrix CW; Chavez-Valdez R; Jansson L et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: A randomized, controlled trial. Pediatrics 123(5): e849-e856, 2009. (42 refs.)

OBJECTIVE. To determine if oral clonidine would reduce the duration of opioid detoxification for neonatal abstinence syndrome. METHODS. Infants with intrauterine exposure to methadone or heroin and neonatal abstinence syndrome (2 consecutive modified Finnegan scores of >= 9) were enrolled at 2 hospitals during 2002-2005 and followed until final hospital discharge. All enrolled infants (80) received oral diluted tincture of opium according to a standardized algorithm and were randomly assigned to receive oral clonidine (1 mu g/kg every 4 hours) (40 infants) or placebo (40 infants). Primary outcome was duration of opioid therapy. Secondary outcomes included the amount of opium required to control symptoms, number of treatment failures, and differences in blood pressure, heart rate, and oxygen saturation. RESULTS. The median length of therapy was 27% shorter in the clonidine group (11 [95% confidence interval: 8-15 days]) than in the placebo group (15 days [95% confidence interval: 12-17 days]). In the clonidine group, 7 infants required restarting opium after initial discontinuation versus none in the placebo group, with the total length of treatment/observation remaining significantly less in the clonidine group. Higher dosages of opium were required by 40% of the infants in the placebo group versus 20% in the clonidine group. Treatment failures occurred in 12.5% of the infants in the placebo group versus none in the clonidine group. Hypertension, hypotension, bradycardia, or desaturations did not occur in either group. Three infants in the clonidine group died as a result of myocarditis, sudden infant death syndrome, and homicide, all after hospital discharge and before 6 months of age. CONCLUSIONS. In this randomized, double-blind trial, adding clonidine to standard opioid therapy for detoxification from in utero exposure to methadone or heroin reduced the duration of pharmacotherapy for neonatal abstinence without causing short-term adverse cardiovascular outcomes. A larger trial is indicated to determine long-term safety.

Bakstad B; Sarfi M; Welle-Strand GK; Ravndal E. Opioid maintenance treatment during pregnancy: Occurrence and severity of neonatal abstinence syndrome. European Addiction Research 15(3): 128-134, 2009. (38 refs.)

Background: Opioid maintenance treatment (OMT) is widely used to treat pregnant women with a history of opioid dependence. This study investigated whether maternal methadone/buprenorphine dose and nicotine use in pregnancy affects the occurrence and duration of neonatal abstinence syndrome (NAS) in the infant. Methods: Forty-one pregnant women from OMT programmes in Norway who gave birth between January 2005 and January 2007 were enrolled in a national prospective study. Thirty-eight women (81% of the population) were interviewed in the last trimester of pregnancy and 3 months after delivery. Data from the European Addiction Severity Index and a questionnaire measuring enrolled birth information were compared with medical records and urine analyses. Results: Treatment requiring NAS occurred in 58% of the methadone-exposed and in 67% of the buprenorphine-exposed infants. There was no significant relationship between a maternal dose of methadone or buprenorphine in pregnancy and NAS treatment duration for the infant. The mean number of cigarettes consumed correlated significantly with NAS treatment duration for the methadone group. Birth weight for the methadone group was approximately 200 g above international findings despite high doses during pregnancy. Conclusions: Maternal methadone/buprenorphine dose predicted neither the occurrence nor the need for NAS treatment for the infant.

Beulens JWJ; Rimm EB; Hendriks HFJ; Hu FB; Manson JE; Hunter DJ; Mukamal KJ. Alcohol consumption and type 2 diabetes: Influence of genetic variation in alcohol dehydrogenase. Diabetes 56(9): 2388-2394, 2007. (47 refs.)

OBJECTIVE-We sought to investigate whether a polymorphism I in the alcohol dehydrogenase 1c (ADH1C) gene modifies the association between alcohol consumption and type 2 diabetes. RESEARCH DESIGN AND METHODS-In nested case-control studies of 640 women with incident diabetes and 1,000 control subjects from the Nurses'Health Study and 383 men with incident diabetes and 382 control subjects from the Health Professionals Follow-Up Study, we determined associations be- tween the ADH1C polymorphism, alcohol consumption, and diabetes risk. RESULTS-Moderate to heavy alcohol consumption (>5 g/day for women and >10 g/day for men) was associated with a decreased risk of diabetes among women (odds ratio [OR] 0.45 [95% CI 0.33-0.63]) but not men (1.08 [0.67-1.75]). ADH1C genotype modified the relation between alcohol consumption and diabetes for women (P-interaction = 0.02). The number of ADH1C*2 alleles, related to a slower rate of ethanol oxidation, attenuated the lower risk of diabetes among women consuming >= 5 g alcohol/day (P-trend = 0.002). These results were not significant among men. Results were similar in pooled analyses (P-interaclon = 0.02) with ORs for diabetes among moderate drinkers of 0.44 (95% CI 0.21-0.94) in ADHlC*1 homozygotes, 0.65 (0.39-1.06) for heterozygotes, and 0.78 (0.50-1.22) for ADH1C*2 homozygotes compared with those for ADH1C*l homozygote abstainers (P-trend = 0.02). CONCLUSIONS-ADH1C genotype modifies the association between alcohol consumption and diabetes. The ADH1C*2 allele, related to a slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. This suggests that the association between alcohol consumption and diabetes may be causal but mediated by downstream metabolites such as acetate rather than ethanol itself.

Bradford BU; Karnitsching J; Powell LL; Garbutt JC. Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol. Alcohol 41(4): 263-270, 2007. (35 refs.)

Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (family history positive [FHP]) were compared to 15 young men without a family history of alcoholism (family history negative [FHN]). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 36 mg/kg/h, compared to FHN subjects, 124 18 mg/kg/h, P = .01. However, FHN subjects increased their rate of metabolism by 10 +/- 27% compared to a decrease of -15 +/- 24% in FHP subjects, P = .007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, P = .0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence.

Chen CC; Yin SJ. Alcohol abuse and related factors in Asia. International Review of Psychiatry 20(5): 425-433, 2008. (78 refs.)

Alcohol problems are a global issue, and the nature of alcohol abuse is very complicated. The susceptibility to alcohol abuse varies greatly from one individual to another and also from one nation to another, depending on the availability of alcohol, a country's regulation related to alcohol, a country's cultural background, religious tradition and its economics. Alcohol dependence is also a complicated disease process. The prevalence of alcohol dependence also varies greatly from one ethnic group to another. Asia is the world's largest and most populous continent. The natural disasters, religious conflicts as well as political disputes cause people lack of opportunity in many countries. People in this region do not consume more alcohol than the people in the rest of the world. The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socio-economic factors, but also biological factors influence drinking behaviour. Findings of functional genetic polymorphism of the major alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) have led to the suggestion that this enzyme system may possibly play a diverse but critical role in alcohol dependence and in the alcohol-related disease process in the different ethnic groups. This paper reviews alcohol problems and related factors. Their management and prevention strategy are discussed.

Cichoz-Lach H; Partycka J; Nesina I; Celinski K; Slomka M; Wojcierowski J. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Scandinavian Journal of Gastroenterology 42(4): 493-498, 2007. (40 refs.)

Objective. To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Material and methods. We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. Results. In the population examined the ADH2*1 allele frequency was 97.97%. The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2/*2 genotype. Conclusions. In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.

Dakeishi M; Murata K; Sasaki M; Tamura A; Iwata T. Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers. Alcohol and Alcoholism 43(2): 143-147, 2008. (36 refs.)

Aims: The objective was to clarify the effect of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) genotypes on the diabetic risk in Japanese workers. Methods: At the time of mandatory health checkup, the ADH2 and ALDH2 genotypes, as well as fasting plasma glucose (FPG) levels, body mass index (BMI), smoking habit, and weekly alcohol intake, were examined in 492 men and 183 women working at motor vehicle dealerships. Results: In using two-way analysis of variance to manipulate ADH2 and ALDH2 genotypes and alcohol intake (70 g/week for men and 35 g/week for women), the FPG level after the adjustment for age, BMI, smoking habit, and another genotype was significantly higher in the men with ADH21/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH21/1 genotype. In contrast, the women with ALDH21/1 genotype had significantly lower FPG levels than those with the other genotypes, but there was no significant difference in the FPG level between the women with and without ADH21/1 genotype. Also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the women. Conclusions: These findings suggest that genotypes of ADH2 and ALDH2 can modify the diabetic risk, irrespective of amounts of alcohol consumed. Also, there may be sex differences in the effect of these enzyme genotypes on glucose metabolism.

Dettling A; Fischer F; Bohler S; Ulrichs F; Skopp G; Graw M et al. Ethanol elimination rates in men and women in consideration of the calculated liver weight. Alcohol 41(6): 415-420, 2007. (52 refs.)

The purpose of the study was to examine gender differences on the pharmacokinetics of ethanol. Sixty-eight healthy men and 64 healthy women with normal body mass indexes received between 0.79 and 0.95 g ethanol/kg body weight in the form of their choice after they had eaten a "typical" breakfast. The aimed concentration for both genders was a blood alcohol concentration C-0 of 0.104 g/dl. Blood samples in the elimination phase were taken in 10- to 20-min intervals beginning after completion of absorption. The maximum blood ethanol concentration was 0.0819 +/- 0.0184 g/dl for women and 0.0841 +/- 0.0155 g/dl for men. The hourly ethanol elimination rate, calculated over a linear function, in blood of 0.0179 +/- 0.0030 g/dl/h in women was significantly higher than the 0.0159 +/- 0.0029 g/dl/h for men (P <.0001). In relation to the liver weight, the hourly elimination rates were 5.008 +/- 0.678 g/kg liver/h for women and 4.854 +/- 0.659 g/kg liver/h for men, and were not statistically significant. The different liver masses as calculated in relation to the distribution volume account for the differing ethanol elimination rates between men and women.

Ding JH; Li SP; Wu JZ; Gao CM; Zhou JN; Cao HX et al. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a Chinese population. Asian Pacific Journal of Cancer Prevention 9(1): 31-35, 2008. (19 refs.)

Objective: To investigate the relationship of alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genotypes as well as alcohol drinking to the susceptibility of primary hepatocellular carcinoma (HCC). Methods: A case-control study including 208 cases of HCC and 208 controls matched with sex, age and residential area was carried out in Taixing city of Jiangsu province, China. Blood samples were collected and tested for ADH2 and ALDH2 genotypes by PCR-RFLP method. Results: There were no significant differences in the frequency of either ADH2 or ALDH2 genotypes between cases and controls. Compared with no-drinkers possessing ALDH21*1 genotypes, drinkers with ALDH21*2 or ALDH22*2 genotypes and cumulative amount of alcohol consumption >3 (Kg * years) were at a significantly higher risk of developing HCC (OR=3.30, 95% CI: 1.24-8.83). In contrast, there was no significant difference in cancer risk between no-drinkers with ADH21*1 and drinkers with ADH2 1*2 or ADH22*2 genotypes. A dose-dependent positive result was found (P=0.044) between cumulative amount of alcohol consumption and the risk of HCC in individuals carrying ALDH21*2 or ALDH22*2 genotypes. Drinkers with cumulative amount of alcohol consumption >3 (Kg * years) who possessed both inactive ALDH2 (ALDH21*2 or ALDH22*2) and inactive ADH (ADH21*2 or ADH22*2) genotypes were not at a significantly higher risk of HCC (adjusted OR=4.26, 95% CI: 0.63-29.08) compared to no-drinkers possessing ADH21*1 and ALDH21*1 genotypes. Compared with individuals possessing ALDH21*1, with negative HBsAg and cumulative amount of alcohol consumption=3 (Kg * years), those with ALDH21*2 or ALDH22*2, positive HBsAg, and cumulative amount of alcohol consumption >3 (Kg * years) had a significantly higher risk of HCC (OR=49.71, 95% CI: 5.51-448.96). Conclusion: These results revealed that it was not ADH2 but ALDH2 polymorphisms that had a significant interaction with heavy alcohol consumption in the development of HCC. This result suggests that to help lower their risk for HCC, persons with ALDH21*2 or ALDH22*2 genotypes should be encouraged to reduce their consumption of alcoholic beverages.

Dryden C; Young D; Hepburn M; Mactier H. Maternal methadone use in pregnancy: Factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG: An International Journal of Obstetrics and Gynaecology 116(5): 665-671, 2009. (43 refs.)

The objectives of this study were to investigate factors associated with the development of neonatal abstinence syndrome (NAS) and to assess the implications for healthcare resources of infants born to drug-misusing women. Retrospective cohort study from 1 January 2004 to 31 December 2006. Inner-city maternity hospital providing dedicated multidisciplinary care to drug-misusing women. Four hundred and fifty singleton pregnancies of drug-misusing women prescribed substitute methadone in pregnancy. Case note review. Development of NAS and duration of infant hospital stay. 45.5% of infants developed NAS requiring pharmacological treatment. The odds ratio of the infant developing NAS was independently related to prescribed maternal methadone dose rather than associated polydrug misuse. Breastfeeding was associated with reduced odds of requiring treatment for NAS (OR 0.55, 95% CI 0.34-0.88). Preterm birth did not influence the odds of the infant receiving treatment for NAS. 48.4% infants were admitted to the neonatal unit (NNU) 40% of these primarily for treatment of NAS. The median total hospital stay for all infants was 10 days (interquartile range 7-17 days). Infants born to methadone-prescribed drug-misusing mothers represented 2.9% of hospital births, but used 18.2% of NNU cot days. Higher maternal methadone dose is associated with a higher incidence of NAS. Pregnant drug-misusing women should be encouraged and supported to breastfeed. Their infants are extremely vulnerable and draw heavily on healthcare resources.

Edenberg HJ. The genetics of alcohol metabolism - Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Research & Health 30(1): 5-13, 2007. (45 refs.)

The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.

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Ehlers CL. Variations in ADH and ALDH in southwest California Indians. Alcohol Research & Health 30(1): 14-17, 2007. (17 refs.)

Native Americans as a group have the highest rates of alcohol-related deaths of all ethnicities in the United States, however, it remains unclear how and why a greater proportion of individuals in some Native American communities develop alcohol-related problems and alcohol use disorders (AUDs). One potential factor that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Researchers have analyzed the frequencies of variants in the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in some Native American populations. So far the studies have yielded no evidence that an ALDH2 variant, which has shown protective effects in other populations, is found in either American Indians or Alaska Natives. A variant of the ALDH1 enzyme that is encoded by the ALDH1A1 *2 allele, however, was found in a small proportion of a group of Southwest California Indians and had a protective effect against alcoholism in that population. Furthermore, a variant of the ADH1B enzyme that is encoded by the ADH1B *3 allele was found in a similar proportion of Southwest California Indians and also was associated with a protective effect. However, these findings do not explain the high prevalence of alcoholism in the tribes investigated.

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Eng MY; Luczak SE; Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: A literature review. Alcohol Research & Health 30(1): 22-27, 2007. (31 refs.)

Variants of three genes encoding alcohol-metabolizing enzymes, the aldehyde dehydrogenase gene ALDH2 and the alcohol dehydrogenase genes ADH1B and ADH1C, have been associated with reduced rates of alcohol dependence. The genotype prevalence of these genes varies in general samples of different Asian ethnic groups. The ALDH2*2 allele appears to be most prevalent in Chinese-American, Han Chinese and Taiwanese, Japanese, and Korean samples. Much lower rates have been reported in Thais, Filipinos, Indians, and Chinese and Taiwanese aborigines. ADH1B*2 is highly prevalent among Asians, with the exception of Indians. ADH1C*1 also is highly prevalent in Asians, but has only been examined in a few studies of Chinese and Korean samples.

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Esmaeili A; Keinhorst AK; Schuster T; Beske F; Schlosser R; Bastanier C. Treatment of neonatal abstinence syndrome with clonidine and chloral hydrate. Acta Paediatrica 99(2): 209-214, 2010. (11 refs.)

Aim: The objective of this retrospective study is to compare the medical treatment of neonatal narcotic abstinence syndrome with clonidine and chloral hydrate with the commonly used combination therapy of morphine and phenobarbital. Methods: From 1998 to 2008, a total of 133 newborns suffering from neonatal narcotic abstinence syndrome were treated at our clinic. All of these patients were born to mothers who had received methadone substitution for drug addiction during the course of pregnancy. Results: Twenty-nine patients received clonidine and chloral hydrate, and 64 patients were treated with morphine and phenobarbital for abstinence syndrome. The duration of treatment was significantly shorter in the clonidine/chloral hydrate group (median: 14 days vs. 35 days). Correspondingly, the period of hospitalization was also considerably shorter in the clonidine/chloral hydrate group (median: 32 days vs. 44 days). In addition, patients in the clonidine/chloral hydrate group exhibited markedly reduced withdrawal symptoms. Conclusion: This study suggests that a treatment of neonatal abstinence syndrome with clonidine in omission of opiates is possible without causing short-term adverse cardiovascular effects. Considering the retrospective design of the study, controlled and prospective trials are needed.

Fisher SJ; Lee IJ; Swaan PW; Eddington ND. Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: In vitro and in vivo studies. Alcoholism: Clinical and Experimental Research 32(1): 162-170, 2008. (57 refs.)

Background: The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. This study examines the effects of the ethanol metabolite, acetaldehyde, on the clinically relevant drug transporter, PEPT1. The metabolism of ethanol and the following acetaldehyde formation is thought to modulate the uptake capacity of PEPT1 within the gastrointestinal tract for a variety of clinically important peptidomimetic drug compounds. Methods: Glycylsarcosine ([H-3]-GlySar), a nonhydrolysable PEPT1 specific substrate was used in our studies. In vitro uptake studies were performed in the Caco-2 and Chinese hamster ovary (CHO)-hPEPT1 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [H-3]-GlySar was measured in male Sprague-Dawley rats that were treated with oral dose of ethanol/disulfiram (5 g/kg / 100 mg/kg) for 6 days. These results were compared to control rats treated with saline, ethanol alone or disulfiram alone. Results: In vitro uptake of [H-3]-GlySar in CHO-hPEPT1 cells treated with 1 mM acetaldehyde was significantly decreased (p < 0.05) as compared to untreated controls. The uptake of [H-3]-GlySar in Caco-2 cell monolayers treated with 1 mM acetaldehyde was also significantly decreased as compared to the untreated control cells. In vivo absorption of [H-3]-GlySar in ethanol treated rats, as measured by AUC(0-12 hours) were decreased by approximately 50% versus the control rat group. Conclusion: The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and, thereby, affects drug bioavailability. To our best knowledge, this is the first report on the effects of an ethanol metabolite on substrate absorption in the gastrointestinal tract, rather than interactions in the liver, which is an under-represented area of research in alcohol pathophysiology.

Gao CM; Takezaki T; Wu JZ; Zhang XM; Cao HX; Ding JH et al. Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males. World Journal of Gastroenterology 14(32): 5078-5083, 2008. (22 refs.)

AIM: To evaluate the relationship between drinking and polymorphisms of alcohol dehydrogenase 2 (ADH2) and/or aldehyde dehydrogenase 2 (ALDH2) for risk of colorectal cancer (CRC) in Chinese males. METHODS: A case-control study was conducted in 190 cases and 223 population-based controls. ADH2 Arg47His (G-A) and ALDH2 Glu487Lys (G-A) genotypes were identified by PCR and denaturing high-performance liquid chromatography (DHPLC). Information on smoking and drinking was collected and odds ratio (OR) was estimated. RESULTS: The ADH2 A/A and ALDH2 G/G genotypes showed moderately increased CRC risk. The age- and smoking-adjusted OR for ADH2 A/A relative to G/A and G/G was 1.60 (95% CI=1.08-2.36), and the adjusted OR for ALDH2 G/G relative to G/A and A/A was 1.79 (95% CI=1.19-2.69). Significant interactions between ADH2, ALDH2 and drinking were observed. As compared to the subjects with ADH2 G and ALDH2 A alleles, those with ADH2 A/A and ALDH2 G/G genotypes had a significantly increased OR (3.05, 95% CI= 1.67-5.57). The OR for CRC among drinkers with the ADH2 A/A genotype was increased to 3.44 (95% CI= 1.84-6.42) compared with non-drinkers with the ADH2 G allele. The OR for CRC among drinkers with the ALDH2 G/G genotype was also increased to 2.70 (95% CI= 1.57-4.66) compared with non-drinkers with the ALDH2 A allele. CONCLUSION: Polymorphisms of the ADH2 and ALDH2 genes are significantly associated with CRC risk. There are also significant gene-gene and gene-environment interactions between drinking and ADH2 and ALDH2 polymorphisms regarding CRC risk in Chinese males.

Gemma S; Vichi S; Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. (review). Neuroscience and Biobehavioral Reviews 31(2): 221-229, 2007. (53 refs.)

Alcohol-related damages on newborns and infants include a wide variety of complications from facial anomalies to neurodevelopmental delay, known as fetal alcohol syndrome (FAS). However, only less than 10% of women drinking alcohol during pregnancy have children with FAS. Understanding the risk factors increasing the probability for newborn exposed in utero to alcohol to develop FAS is therefore a key issue. The involvement of genetics as a one risk factor in FAS has been suggested by animal models and by molecular epidemiological studies on different populations, bearing allelic variants for those enzymes, such as ADH e CYP2E1, involved in ethanol metabolism. Indeed, one of the major factors determining the peak blood alcohol exposure to the fetus is the metabolic activity of the mother, in addition to placental and fetal metabolism, explaining, at least partially, the risk of FAS. The different rates of ethanol metabolism may be the result of genetic polymorphisms, the most relevant of which have been described in the paper.

Grassi MC; Cioce AM; Giudici FD; Antonilli L; Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: A pilot study. Pharmacological Research 55(2): 117-121, 2007. (38 refs.)

Cocaine abusers frequently report taking the drug in association with alcohol. This combined intake leads to the synthesis of cocaethylene, an active metabolite with effects similar to those of cocaine, but more prolonged. Since pharmacological effects of cocaethylene may partially account for the habit of cocaine abusers to take the drug in combination with ethanol, a main therapeutic goal in these patients should be making body fluids negative for cocaethylene. This randomized controlled open study conducted on 12 subjects co-abusers of cocaine and alcohol, evaluates the efficacy of a 12-week pharmacological treatment with Disulfiram (DIS) 400 mg daily or Naltrexone (NTX) 50 mg daily associated with Cognitive Behaviour Therapy (CBT), as compared to CBT alone, in terms of: (i) stay in treatment; (ii) drug-free urinalyses for cocaine and cocaethylene; (iii) reduction of alcohol and cocaine craving. Data presented in this study are restricted to the first 4 weeks of treatment when all the enrolled subjects were still available for examination. In fact, of the 12 subjects enrolled in the study only 4 (33%) completed the 12-week treatment. Of these, three were in the CBT group and one in the NTX/CBT group. Results show that CBT treated subjects remained in treatment longer than those assigned to either DIS/CBT or NTX/CBT therapies. However, during the first 4 weeks of treatment, CBT-group urine tested positive almost always for both cocaine and cocaethylene. In contrast, both DIS/CBT and NTX/CBT treatments were associated to a statistically significant reduction, of positive urinalysis for both cocaine and cocaethylene, with respect to CBT alone. Moreover, across the first 4 weeks of treatment DIS/CBT and NTX/CBT treated subjects maintained lower scores at Visual Analogue Scales (VAS) for both cocaine and alcohol craving than subjects receiving CBT alone. This pilot study suggests that the transient efficacy of pharmacological treatments in maintaining subjects drug free, does not add to the capability of CBT to retain them in treatment.

Harrigan GG; Maguire G; Boros L. Metabolomics in alcohol research and drug development. Alcohol Research & Health 31(1): 26-35, 2008. (37 refs.)

Developers of new medications need to describe and predict the functional attributes of test compounds administered to cells, animals, and humans. Today, researchers increasingly appreciate the role that intermediary products (i.e., metabolites) generated in the course of various metabolic pathways play in both health and disease states and how their analysis can support development of new medications. Advances in analytical and computational techniques have facilitated the rise of new and powerful tools for measuring metabolic and biochemical pathways in such complex systems. Metabolomics -- a systems biology approach to characterizing metabolites produced in biochemical pathways -- is contributing to many studies of disease progression and treatment, although it has not yet been extensively applied in research on metabolic perturbations associated with alcohol abuse. However, numerous metabolomic approaches may contribute to alcohol-related research, as illustrated by studies on alcohol-related metabolic dysfunctions such as (1) alterations in fat metabolism and (2) thiamine deficiency. By further increasing the number and types of metabolites that can be measured in a given biological sample, metabolomic approaches may be able to help define the role of the many different metabolic pathways affected by alcohol abuse and support discovery and development of novel medications for the treatment of alcoholism and related conditions.

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Hey H; Schmedes A; Nielsen AA; Winding P; Gronbaek H. Effects of five different alcoholic drinks on patients with Crohn's disease. Scandinavian Journal of Gastroenterology 42(8): 968-972, 2007. (16 refs.)

Objective. Many patients with Crohn's disease ( CD) complain of abdominal discomfort after alcohol intake. The aim of the present study was to investigate the effect of ethanol and sugar content in five different alcoholic drinks on abdominal discomfort in patients with CD. Material and methods. In a crossover study, two weeks apart, 12 healthy individuals and 20 patients with CD in remission consumed randomly red wine, white wine, Smirnoff Ice, Elephant Beer and pure ethanol. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180 min. A self-reported pain symptom score was used. Results. There was no difference between CD patients and healthy individuals in the area under the curve (AUC) for the ethanol concentration after intake of the five different drinks. The plasma AUC for glucose in the CD patients after intake of Smirnoff Ice and Elephant beer was significantly increased (p < 0.05) in comparison with that in the remaining three alcoholic drinks. Abdominal pain manifestations were significantly more pronounced in CD patients following intake of Smirnoff Ice and Elephant beer, with their higher sugar concentration, compared with intake of the remaining three drinks (p < 0.05). Conclusions. The present study shows no difference in alcohol absorption between CD patients and controls. The alcoholic drinks Smirnoff Ice and Elephant beer have an increased effect on self-reported abdominal pain in CD patients, probably due to the high sugar content in these drinks.

Hiraki A; Matsuo K; Wakai K; Suzuki T; Hasegawa Y; Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Science 98(7): 1087-1091, 2007. (22 refs.)

Alcohol consumption is a strong risk factor for squamous cell carcinoma of the head and neck (SCCHN). The genetic polymorphisms aldehyde dehydrogenase2 (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in the Japanese population. To clarify the significance of these polymorphisms in SCCHN carcinogenesis, we conducted a matched case-control study with 239 incident SCCHN subjects and 716 non-cancer controls. Both ADH2 Arg/Arg and ALDH2 Glu/Lys were found to be independently associated with increased risk, with odds ratios (OR) of 2.67 (95% confidence interval [CI] 1.51-4.57) and 1.66 (95% CI 1.20-2.31), respectively. Further, compared with subjects having both ADH2 His/His and ALDH2 Glu/Glu, the adjusted OR and its 95% CI for those with both ADH2 Arg/Arg and ALDH2 Glu/Lys was 5.00 (2.32-10.71) in all subjects. This combination effect was evident in heavy drinkers (OR 11.3, 95% CI 2.97-43.3) but not in moderate or non-drinkers. Statistically significant gene-environment interactions between the two polymorphisms and drinking level were seen (ADH2 P = 0.035, ALDH2, P = 0.013). Furthermore, we also found a statistically significant gene-gene interaction between the two polymorphisms (P = 0.042). In conclusion, this case-control study showed a significantly increased risk of SCCHN in subjects with the ADH2 Arg/Arg and ALDH2 Glu/Lys polymorphisms in a Japanese population. In addition, our results also demonstrated that this risk was associated with significant gene-gene interactions between ADH2 and ALDH2 polymorphisms, as well as gene-environment interactions between these polymorphisms and alcohol drinking.

Hosono S; Matsuo K; Kajiyama H; Hirose K; Suzuki T; Hiraki A et al. Reduced risk of endometrial cancer from alcohol drinking in Japanese. Cancer Science 99(6): 1195-1201, 2008. (38 refs.)

The role of alcohol consumption in the etiology of endometrial cancer has not been clarified. To examine the association between alcohol consumption and endometrial cancer risk, we conducted a case-control study with 148 histologically diagnosed incident endometrial cancer cases and 1468 matched non-cancer controls. Median consumption of alcohol was only 19.3 g/week among cases who drank and 28.2 g/week among controls who drank. These values are lower than in Western countries. Relative risk was analyzed in subjects classified into four groups according to weekly alcohol consumption (non-drinkers, 1-24 g/week, 25-175 g/week, and > 175 g/week). Confounder-adjusted odds ratios for those consuming alcohol at < 25 g/week, 25-175 g/week, and > 175 g/week compared to non-drinkers were 0.79 (95% confidence interval (CI), 0.49-1.28), 0.42 (95% CI, 0.23-0.79), and 0.47 (95% CI, 0.14-1.58), respectively. Further analysis was conducted concerning self-reported physical reaction to alcohol. Among women without flushing after drinking, a significant inverse association between risk and alcohol intake was seen (trend P = 0.001). In contrast, no protective effect of alcohol was seen among women who experience flushing after drinking. These results suggest the presence of an inverse association between alcohol drinking and endometrial cancer risk among Japanese women, and that this association is evident among those without flushing. Further investigation of these findings is warranted.

Husemoen LLN; Fenger M; Friedrich N; Tolstrup JS; Fredriksen SB; Linneberg A. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcoholism: Clinical and Experimental Research 32(11): 1984-1991, 2008. (59 refs.)

Background: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking. In a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. Methods: The study population consisted of 1,216 Danish men and women aged 15-77 years participating in a health examination in 1998. The health examination included a self-administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume (E-MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. Results: Self-reported alcohol drinking was significantly associated with increasing levels of ALAT, E-MCV, high-density lipoprotein cholesterol, and blood pressure. The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge-drinking, and the ALDH1b1 ala69val polymorphism was associated with diastolic blood pressure. We did not find any statistically significant interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. Conclusions: In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene-environment interactions. More large-scale epidemiologic studies are needed to confirm theses results and to further investigate genetic susceptibility to the effects of alcohol drinking.

Jelski W; Zalewski B; Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer. Journal of Clinical Laboratory Analysis 22(3): 204-209, 2008. (20 refs.)

The principal enzymes catalyzing the conversion of ethanol to acetate are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The activities of these enzymes are elevated in the serum during the course of alcoholism or cirrhosis. In previous investigations we have found elevated levels of ADH, ALDH, and class I ADH activity in liver cancer cells. It can suggest that these changes may be reflected by enzyme activity in the serum. In this work, the activity of ADH isoenzymes, and ALDH in the sera of patients with liver cancer was measured. Serum samples were taken from 64 patients (28 drinkers, 36 nondrinkers), with liver cancer. 25 patients had primary and 39 metastatic liver tumors. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorimetric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorimetric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class I ADH isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased about 51% (2.94 mU/L) in the comparison to the control level (1.43 mU/L). The activity of the class I ADH isoenzyme was significantly higher in the sera of patients with metastatic tumors than with primary cancers. The activity of this class in the sera of drinkers and group of moderate drinkers was significantly higher in comparison to the control group and higher in the sera of heavy drinkers when compared with moderate drinking patients. The total ADH activity was significantly higher (44%) among patients with cancer than healthy ones. The activity of class I ADH isoenzymes was elevated only in the serum of patients with metastatic liver cancer. This increase of activity seems to be caused by the enzyme released from liver cancer cells and primary tumors originating in other organs.

Kapur BM; Vandenbroucke AC; Adamchik Y; Lehotay DC; Carlen PL. Formic acid, a novel metabolite of chronic ethanol abuse, causes neurotoxicity, which is prevented by folic acid. Alcoholism: Clinical and Experimental Research 31(12): 2114-2120, 2007. (73 refs.)

Background: Methanol is endogenously formed in the brain and is present as a congener in most alcoholic beverages. Because ethanol is preferentially metabolized over methanol (MeOH) by alcohol dehydrogenase, it is not surprising that MeOH accumulates in the alcohol-abusing population. This suggests that the alcohol-drinking population will have higher levels of MeOH's neurotoxic metabolite, formic acid (FA). FA elimination is mediated by folic acid. Neurotoxicity is a common result of chronic alcoholism. This study shows for the first time that FA, found in chronic alcoholics, is neurotoxic and this toxicity can be mitigated by folic acid administration. Objective: To determine if FA levels are higher in the alcohol-drinking population and to assess its neurotoxicity in organotypic hippocampal rat brain slice cultures. Methods: Serum and CSF FA was measured in samples from both ethanol abusing and control patients, who presented to a hospital emergency department. FA's neurotoxicity and its reversibility by folic acid were assessed using organotypic rat brain hippocampal slice cultures using clinically relevant concentrations. Results: Serum FA levels in the alcoholics (mean +/- SE: 0.416 +/- 0.093 mmol/l, n = 23) were significantly higher than in controls (mean +/- SE: 0.154 +/- 0.009 mmol/l, n = 82) (p < 0.0002). FA was not detected in the controls' CSF (n = 20), whereas it was > 0.15 mmol/l in CSF of 3 of the 4 alcoholic cases. Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to the rat brain slice cultures caused neuronal death as measured by propidium iodide staining. When folic acid (1 mu mol/l) was added with the FA, neuronal death was prevented. Conclusions: Formic acid may be a significant factor in the neurotoxicity of ethanol abuse. This neurotoxicity can be mitigated by folic acid administration at a clinically relevant dose.

Kim DJ; Choi IG; Park BL; Lee BC; Ham BJ; Yoon S et al. Major genetic components underlying alcoholism in Korean population. Human Molecular Genetics 17(6): 854-858, 2008. (20 refs.)

Alcohol metabolism is one of the biological determinants that could significantly be influenced by genetic polymorphisms in alcohol-metabolism genes. Alcohol dehydrogenase (ADH) converts alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH) converts acetaldehyde to acetate. The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde, respectively. The protective allele of ADH1B (ADH1B*47His) encodes for a rapid ethanol-metabolizing enzyme, and the susceptible allele of the ALDH2 (ALDH2*487Lys) is strongly associated with decreased rate of metabolizing acetaldehyde. However, the combined genetic effects of both functional polymorphisms have not been clarified. The combined analysis of two polymorphisms among a Korean population (n = 1,032) revealed dramatic genetic effects on the risk of alcoholism. Individuals bearing susceptible alleles at both loci have 91 times greater risk for alcoholism [odds ratio (OR) = 91.43, P = 1.4 x 10(-32)] and individuals bearing one susceptible and one protective allele at either loci have 11 times greater risk (OR = 11.40, P = 3.5 x 10(-15)) compared with subjects who have both protective alleles. The attributable fraction of those genetic factors, calculated based on population controls, indicates that alcoholism in 86.5% of alcoholic patients can be attributed to the detrimental effect of ADH1B*47Arg and/or ALDH2*487Glu in Korean population.

Lim S; Prasad MR; Samuels P; Gardner DK; Cordero L. High-dose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome. American Journal of Obstetrics and Gynecology 200(1): Article Number: 70.e1, 2009. (18 refs.)

OBJECTIVE: The purpose of this study was to examine high-dose methadone in pregnant women and its effect on the duration of neonatal abstinence syndrome. STUDY DESIGN: This was a retrospective chart review of 68 neonates and their mothers who received methadone therapy during pregnancy. The last dosage of maternal methadone just before delivery and the length of treatment for neonatal abstinence syndrome were examined with an analysis of variance model. RESULTS: When the data were analyzed for methadone dosages as a continuous variable, each 1-mg increase in the last maternal methadone dosage before delivery was associated with an additional 0.18 days of infant treatment for neonatal abstinence syndrome (P < .001; 95% CI, 0.112-0.255). In other words, every increase of 5.5 mg of methadone in the mother was associated statistically with 1 additional day of neonatal abstinence syndrome treatment for the infant. Gestational age at delivery and birthweight were not statistically significant. CONCLUSION: Higher doses of maternal methadone were associated with an increase in diagnosis and longer duration of neonatal abstinence syndrome.

Lowe ED; Gao GY; Johnson LN; Keung WM. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. Journal of Medicinal Chemistry 51(15): 4482-4487, 2008. (50 refs.)

The ALDH2 *2 gene encoding the inactive variant form of mitochondrial aldehyde dehydrogenase (ALDH2) protects nearly all carriers of this gene from alcoholism. Inhibition of ALDH2 has hence become a possible strategy to treat alcoholism. The natural product 7-0-glucosyl-4'-hydroxyisoflavone (daidzin), isolated from the kudzu vine (Peruraria lobata), is a specific inhibitor of ALDH2 and suppresses ethanol consumption. Daidzin is the active principle in a herbal remedy for "alcohol addiction" and provides a lead for the design of improved ALDH2. The structure of daidzin/ALDH2 in complex at 2.4 A resolution shows the isoflavone moiety of daidzin binding close to the aldehyde substrate-binding site in a hydrophobic cleft and the glucosyl function binding to a hydrophobic patch immediately outside the isoflavone-binding pocket. These observations provide an explanation for both the specificity and affinity of daidzin (IC50 = 80 nM) and the affinity of analogues with different substituents at the glucosyl position.

Matsuo K; Hiraki A; Hirose K; Ito H; Suzuki T; Wakai K et al. Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese. Human Mutation 28(5): 506-510, 2007. (33 refs.)

A linkage disequilibrium (LD) between the alcohol-dehydrogenase 1B (ADH1B) and alcohol-dehydrogenase 1C (ADH1C) polymorphisms adds complexity to differentiating the significance of these two genetic polymorphisms on drinking behavior and alcoholism. We have recently shown the importance of the ADH1B polymorphism on habitual drinking in the Japanese population; however, the issue regarding the LD between the ADH1B and ADH1C polymorphisms remains to be clarified. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese individuals. Drinking behavior was examined with regard to haplotypes of the ADH1B and ADH1C polymorphisms. Strength of association was assessed by sex and alaehyde-dehydrogenase 2 (ALDH2) adjusted odds ratios (OR) and their 95% confidence intervals (CIs) for the haplotype of the ADH1B and ADH1C polymorphisms. The ORs for habitual drinking were significant for ADH1B*2(rapid), ADHIC*2(slow) (OR = 1.03; 95% CI: 1.01-1.05), ADHIB*1 (slow)-ADH1C*1 (rapid) (OR = 1.15; 95% CI: 1.14-1.16), and ADH1B*1 (slow)-ADH1C*2 (slow) (OR= 1.31; 95% CI: 1.29-1.32) compared with ADH1B*2 (rapid) ADH1C*1 (rapid). This trend was evident among mates. Similarly, a significantly increased risk of heavy drinking was observed for each haplotype compared with ADH1B*2 (rapid)-ADH1C*1 (rapid). In conclusion, this study showed a significant impact of the ADH1C polymorphism on habitual drinking, regardless of the ADH1B/ALDH2 polymorphisms.

Meier P; Seitz HK. Age, alcohol metabolism and liver disease. Current Opinion in Clinical Nutrition and Metabolic Care 11(1): 21-26, 2008. (43 refs.)

Purpose of review: Alcohol consumption among the elderly has increased. Alcohol metabolism changes with age and the elderly are more sensitive to the toxic effects; this increased consumption is therefore of great clinical relevance. Recent findings: Metabolism of ethanol changes with advancing age because activity of the enzymes involved, such as alcohol and acetalclehyde dehydrogenase and cytochrome P-4502E1, diminish with age. The water distribution volume also decreases with age. Both lead to increased blood concentrations of ethanol. Also, elderly people take more drugs, and ethanol and these drugs may interact; therefore, alcohol consumption can modify serum drug concentrations and their toxicity. Finally, elderly people may suffer more frequently from other types of liver disease, and alcohol may exacerbate these. Summary: Over recent decades alcohol consumption has increased among those who are older than 65 years. Alcohol is more toxic in the ageing organism because of changes in its metabolism, distribution and elimination, which lead to central nervous system effects at lower levels of intake; also, ageing organs such as brain and liver are more sensitive to the toxicity of alcohol. For these reasons, alcohol should be used in moderation, especially among those of older age.

Mello T; Ceni E; Surrenti C; Galli A. Alcohol induced hepatic fibrosis: Role of acetaldehyde. (review). Molecular Aspects of Medicine 29(1-2): 17-21, 2008. (37 refs.)

Alcohol abuse is one of the major causes of liver fibrosis worldwide. Although the pathogenesis of liver fibrosis is a very complex phenomenon involving different molecular and biological mechanisms, several lines of evidence established that the first ethanol metabolite, acetaldehyde, plays a key role in the onset and maintenance of the fibrogenetic process. This review briefly summarizes the molecular mechanisms underlying acetaldehyde pro-fibrogenic effects. Liver fibrosis represents a general wound-healing response to a variety of insults. Although mortality due to alcohol abuse has been constantly decreasing in the past 20 years in Southern Europe and North America, in several Eastern-European countries and Great Britain Alcoholic Liver Disease (ALD) shows a sharply increasing trend [Bosetti, C., Levi, F., Lucchini, F., Zatonski, W.A., Negri, E., La, V.C., 2007. Worldwide mortality from cirrhosis: an update to 2002. J. Hepatol. 46, 827-839]. ALD has a complex pathogenesis, in which acetaldehyde (AcCHO), the major ethanol metabolite, plays a central role. Ethanol is mainly metabolized in the liver by two oxidative pathways. In the first one ethanol is oxidized to acetaldehyde by the cytoplasmic alcohol dehydrogenase enzyme (ADH), acetaldehyde is then oxidized to acetic acid by the mitochondrial acetaldehyde dehydrogenase (ALDH). The second pathway is inducible and involves the microsomal ethanol-oxidizing system (MEOS), in which the oxidation of ethanol to acetaldehyde and acetic acid also leads to generation of reactive oxygen species (ROS). Chronic ethanol consumption significantly inhibits mitochondrial ALDH activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in a striking increase of tissue and plasma acetaldehyde levels [Lieber, C.S., 1997. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59-84]. This review will focus oil the molecular mechanisms by which acetaldehyde promote liver fibrosis.

Minegishi Y; Tsukino H; Muto M; Goto K; Gernma A; Tsugane S et al. Susceptibility to lung cancer and genetic polymorphisms in the alcohol metabolite-related enzymes alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 in the Japanese population. Cancer 110(2): 353-362, 2007. (42 refs.)

BACKGROUND. it is believed that acetaldehyde plays an important role in alcohol-related carcinogenesis; although current epidemiologic studies have provided inconsistent findings on the association between alcohol consumption and the risk of lung cancer. METHODS. To clarify the hypothesis that genetic polymorphisms in alcohol-metabolizing enzymes may influence susceptibility to lung cancer, the authors conducted a hospital-based case-control study and examined genetic polymorphisms in the alcohol dehydrogenase 3, aldehyde dehydrogenase 2 (ALDH(2)), and cytochrome P450 2131 genes in 505 patients with histologically confirmed lung cancer and in a group of 256 noncancer controls who provided complete cigarette and alcohol consumption histories. Genotyping was conducted by polymerase chain reaction-restriction fragment-length polymorphism assay. RESULTS. A significant association was noted between alcohol consumption and lung cancer risk. Thus, using the median value for the controls as the cut-off point, the odds ratios (OR) for light and heavy drinkers were 1.76 and 1.95, respectively (P for trend =.012), compared with nondrinkers. In addition, there was a significant trend toward increased risk of lung cancer in drinkers with ALDH2 variant alleles (P for trend <.0001). The adjusted OR for heavy drinkers was 6.15 compared with nondrinkers. Regarding associations between histologic type and genotypes, the ALDH(2) variant allele was significantly less common in patients who had adenocarcinoma compared with controls. CONCLUSIONS. The current observations suggested a positive association between alcohol consumption and the risk of lung cancer: Drinking may increase the risk, especially among individuals who have the variant ALDH(2) alleles.

Mizoue T; Inoue M; Wakai K; Nagata C; Shimazu T; Tsuji I et al. Alcohol drinking and colorectal cancer in Japanese: A pooled analysis of results from five cohort studies. American Journal of Epidemiology 167(12): 1397-1406, 2008. (40 refs.)

Colorectal cancer is an alcohol-related malignancy; however, the association appears to be stronger among Asian populations with a relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant. To examine the association between alcohol consumption and colorectal cancer in Japanese, the authors analyzed original data from five cohort studies that measured alcohol intake using validated questionnaires at baseline. Hazard ratios were calculated in the individual studies, with adjustment for a common set of variables, and then combined using a random-effects model. During 2,231,010 person-years of follow-up (ranging variously from 1988 to 2004), 2,802 colorectal cancer cases were identified. In men, multivariate-adjusted pooled hazard ratios for alcohol intakes of 23-45.9 g/day, 46-68.9 g/day, 69-91.9 g/day, and >= 92 g/day, compared with nondrinking, were 1.42 (95% confidence interval (CI): 1.21, 1.66), 1.95 (95% CI: 1.53, 2.49), 2.15 (95% CI: 1.74, 2.64), and 2.96 (95% CI: 2.27, 3.86), respectively (p for trend < 0.001). The association was evident for both the colon and the rectum. A significant positive association was also observed in women. One fourth of colorectal cancer cases in men were attributable to an alcohol intake of >= 23 g/day. An alcohol-colorectal cancer association seems to be more apparent in Japanese than in Western populations. Whether this difference can be ascribed to genetic or environmental factors needs to be clarified.

Moore S; Montane-Jaime LK; Carr LG; Ehlers CL. Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago. Alcohol Research & Health 30(1): 28-30, 2007. (12 refs.)

The population of Trinidad and Tobago is composed mainly of people of East Indian (indo-Trinidadians) and African (Afro-Trinidadians) ancestry. Differences in alcoholism rates exist between these two ethnic groups, and researchers have investigated whether these differences can be explained in part by variations in the genes encoding the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) III and IC, and aldehyde dehydrogenase (ALDH) I and 2. Studies have demonstrated that a certain variant of the gene encoding ADH1B (ADH1B*3) is associated with a reduced risk of alcoholism in Afro- Trinidadians, as is a variant of the gene encoding ADH1C (i.e., ADH1C*1) in Indo-Trinidadians. An ALDH2 variant shown to have protective effects primarily in East Asians was not found in either Trinidadian ethnic group. However, a variant in the gene encoding cytosolic ALDH1A (i.e. ALDH1A1*1/*2) was found to be associated with an increase in alcohol dependence in Indo-Trinidadians.

Public Domain

O'Donnell M; Nassar N; Leonard H; Hagan R; Mathews R; Patterson Y et al. Increasing prevalence of neonatal withdrawal syndrome: Population study of maternal factors and child protection involvement. Pediatrics 123(4): E614-E621, 2009. (28 refs.)

OBJECTIVES. Illicit drug use during pregnancy is an important public health issue, with adverse effects on the newborn and implications for subsequent parenting. The aim of this study was to measure the birth prevalence of neonatal withdrawal syndrome over time, associated maternal characteristics and child protection involvement. METHODS. This is a retrospective cohort study that used linked health and child protection databases for all live births in Western Australia from 1980 to 2005. Maternal characteristics and mental health- and assault-related medical history were assessed by using logistic regression models. RESULTS. The birth prevalence of neonatal withdrawal syndrome increased from 0.97 to a high of 42.2 per 10 000 live births, plateauing after 2002. Mothers with a previous mental health admission, low skill level, Aboriginal status or who smoked during pregnancy were significantly more likely to have an infant with neonatal withdrawal syndrome. These infants were at greater risk for having a substantiated child maltreatment allegation and entering foster care. Increased risk for maltreatment was associated with mothers who were aged <30 years, were from socially disadvantaged backgrounds, Aboriginal status, and had a mental health- or assault-related admission. CONCLUSIONS. There has been a marked increase in neonatal withdrawal syndrome in the past 25 years. Specific maternal characteristics identified should facilitate planning for early identification and intervention for these women. Findings demonstrate an important pathway into child maltreatment and highlight the need for well-supported programs for women who use illicit drugs during pregnancy as well as the support after birth. Pediatrics 2009; 123: e614-e621

Patrick KS; Straughn AB; Minhinnett RR; Yeatts SD; Herrin AE; DeVane CL et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clinical Pharmacology & Therapeutics 81(3): 346-353, 2007. (31 refs.)

This study explores the hypotheses that: (1) ethanol will interact with di-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dI-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P < 0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C-max (+/- SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). I-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where I-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P < 0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C-max and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

Pavlic M; Libiseller K; Grubwieser P; Ulmer H; Sauper T; Rabl W. Another 'soberade' on the market: does Outox keep its promise? Wiener Klinische Wochenschrift 119(3-4): 104-111, 2007. (33 refs.)

Objective: Several products are being widely promoted for reduction of the concentration of alcohol in the human body. One of these preparations, the fructose soft drink Outox, claims to noticeably increase the alcohol elimination rate (beta 60). Theories to explain this 'fructose effect' are based on the assumption that NAD+, the coenzyme for alcohol dehydrogenase, is regenerated faster in the presence of fructose. Method: A randomized double-blind, placebo-controlled cross-over study was performed with 30 volunteers in two drinking sessions each. Under strictly identical conditions, the same amount of alcohol was consumed, followed by the consumption of either 250 ml Outox or 250 ml placebo. Periodical measurements of blood (BAC), breath (BrAC) and urine alcohol concentration (UAC) were performed. Results: Analyses revealed a significant difference (P < 0.0001) between the mean alcohol levels of the Outox and the placebo drinking sessions. The overall mean BAC difference was 0.077 g/l (BAC 0.748 g/l without vs 0.671 g/l with Outox), equivalent to 10.3%. The mean BrAC difference was 0.045 mg/l (BrAC 0.314 mg/l without vs 0.269 mg/l with Outox), equivalent to 14.3%. Differences were lower for women than for men. A significant difference between the alcohol elimination rates (beta 60) was not found. Conclusions: The results show that the soft drink Outox may decrease the alcohol concentration by about 10%. However, BAC and BrAC differences are rather a consequence of slower gastric absorption of alcohol, because Outox does not increase the alcohol elimination rate. Our study demonstrates that the claim of Outox or other fructose drinks to work as a 'soberade' cannot be proven from a scientific point of view. It should be the task of physicians to warn potential consumers, especially in connection with drinking and driving.

Pepino MY; Steinmeyer AL; Mennella JA. Lactational state modifies alcohol pharmacokinetics in women. Alcoholism: Clinical and Experimental Research 31(6): 909-918, 2007. (62 refs.)

Background: Given the physiological adaptations of the digestive system during lactation, the present study tested the hypothesis that lactation alters alcohol pharmacokinetics. Methods: Lactating women who were exclusively breastfeeding a 2- to 5-month-old infant and 2 control groups of nonlactating women were studied. The first control group consisted of women who were exclusively formula-feeding similarly aged infants, whereas the other consisted of women who had never given birth. A within-subjects design study was conducted such that women drank a 0.4 g/kg dose of alcohol following a 12-hour overnight fast during one test session (fasted condition) or 60 minutes after consuming a standard breakfast during the other (fed condition). Blood alcohol concentration (BAC) levels and mood states were obtained at fixed intervals before and after alcohol consumption. Results: Under both conditions, the resultant BAC levels at each time point were significantly lower and the area under the blood alcohol time curve were significantly smaller in lactating women when compared with the 2 groups of nonlactating women. That such changes were due to lactation per se and not due to recent parturient events was suggested by the finding that alcohol pharmacokinetics of nonlactating mothers, who were tested at a similar time postpartum, were no different from women who had never given birth. Despite lower BAC levels in lactating mothers, there were no significant differences among the 3 groups of women in the stimulant effects of alcohol. However, lactating women did differ in the sedative effects of alcohol when compared with nulliparous but not formula-feeding mothers. That is, both groups of parous women felt sedated for shorter periods of time when compared with nulliparous women. Conclusions: The systemic availability of alcohol was diminished during lactation. However, the reduced availability of alcohol in lactating women did not result in corresponding changes in the subjective effects of alcohol.

Rozin AP; Attias J; Presser D; Rosenberg H; Moscovitz M; Bentur Y. Alcohol poisoning and venous hyperoxia. Toxicology Mechanisms and Methods 18(9): 745-750, 2008. (25 refs.)

Venous PCO2 and PO2 in the presence of normal arterial PCO2 and PO2 in patients with alcoholic intoxication have not been previously evaluated. The objective of this study was to compare arterial and venous blood gases in patients with alcoholic intoxication and healthy controls. Sixteen patients with alcoholic intoxication and 20 controls underwent simultaneous blood sampling from a radial artery and an antecubital vein for acid-base analysis. Osmolality and ethanol blood concentration was estimated. Elevated venous pO(2) were found in 56% of patients with alcoholic poisoning compared with 15% of controls. A formula was found describing possible arterio-venous shunt accounting for elevated venous pO(2) and enabling calculation of the relevant venous carbon dioxide content and CO2 product. The values of the venous pO(2) and arterio-venous shunt were more significant in the alcohol group than in controls (p = 0.002, p = 0.001, respectively). Percentage of patients with a-v shunts was significantly higher in the alcohol group (81%) than in controls (25%) (p = 0.002, OR 2.6, 95% CI 0.13-6.52). The relevant venous CO2 and CO2 product had the non-significant trend to be higher in the alcohol group. In conclusion, this study reports ethanol-induced venous pO(2) and pCO(2) elevation. This may be associated with the effects of tissue perfusion stealing and high oxygen consumption. On the other hand, possible beneficial consequences may occur: acceleration of alcohol elimination and reduction of alcohol-induced tissue damage.

Sarfi M; Martinsen H; Bakstad B; Roislien J; Waal H. Patterns in sleep-wakefulness in three-month old infants exposed to methadone or buprenorphine. Early Human Development 85(12): 773-778, 2009. (42 refs.)

Background: Infants exposed to opioides in-utero frequently demonstrate withdrawal symptoms in the neonatal period and have difficulties with state regulation. Aim: This study examines sleep-wakefulness-distress patterns as indicators of regulatory mechanisms at 3 months of age. Participants: A national infant cohort (N=35) born to women in high-dose maintenance treatment during pregnancy and a comparison group (N=36) of low-risk infants born in the same period. Outcome measures: Distributions and frequencies of sleep, wakefulness and distress measured in hours and episodes on sleep charts recorded by the mothers in the two groups. Results: Women in maintenance treatment were monitored closely during pregnancy to avoid illicit drug use and to be prepared for motherhood. They were also offered residential treatment before pregnancy and after the child was born. There were no statistical differences between the two groups in any of the 10 measures reflecting diurnal and nocturnal rhythmicity at 3 months despite of neonatal abstinence syndrome in 47% of the exposed infants and significant differences in infant characteristics with respect to birth weight, gestational age and maternal characteristics. Conclusions: Follow-up procedures combining drug monitoring and counseling during pregnancy and in the first months after birth enhance the development of state regulation in terms of sleep-wakefulness patterns.

Scott DM; Taylor RE. Health-related effects of genetic variations of alcohol-metabolizing enzymes in African Americans. Alcohol Research & Health 30(1): 18-21, 2007. (27 refs.)

Alcohol metabolism involves two key enzymes-alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are several types of ADH and ALDH, each of which may exist in several variants (i.e., isoforms) that differ in their ability to break down alcohol and its toxic metabolite acetaldehyde. The isoforms are encoded by different gene variants (i.e., alleles) whose distribution among ethnic groups differs. One variant of ADH Is ADH1B, which is encoded by several alleles. An allele called ADH1B*3 is unique to people of African descent and certain Native American tribes. This allele is associated with more rapid breakdown of alcohol, leading to a transient accumulation of acetaldehyde. African Americans carrying this allele are less likely to have a family history of alcoholism and experience a less rewarding subjective response to alcohol. Moreover, children of mothers with this allele are less vulnerable to alcohol-related birth defects. The enzyme ALDH1 also is encoded by several alleles. Two of these alleles that are found in African Americans - ALDH1 A1 *2 and ALDH1 A1 *3 - may be associated with a reduced risk of alcoholism.

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Seitz HK; Becker P. Alcohol metabolism and cancer risk. Alcohol Research & Health 30(1): 38+, 2007. (31 refs.)

Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol-related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers.

Public Domain

Simic M; Tasic M. The relationship between alcohol elimination rate and increasing blood alcohol concentration. Calculated from two consecutive blood specimens. Forensic Science International 172(1): 28-32, 2007. (26 refs.)

In the period 1991-2005, a blood-alcohol concentration (BAC) analysis was carried out at the Institute of forensic medicine in Novi Sad including 2023 two consecutive blood specimens using the Headspace Gas Chromatography method. Cases with no alcohol concentration values, as well as cases where blood samples were taken within 1 h after the criminal act, were not taken into consideration. Following this rule, 1198 cases were considered in this study and all samples were grouped in 29 ranges of BAC(1) of Delta(BAC) = 0.1 g/kg, starting from 0.1-0.19 g/kg to 2.9-2.99 g/kg of absolute alcohol. Gathered results and elimination curve differ from the zero-order model of elimination proposed by Widmark and point to an elimination process similar to a well-known Michaelis-Menten elimination kinetics model and its variants. Results reported in this study show dependence of alcohol elimination rate (beta(60)-slope) and BAC value. The analysis of beta(60)-slope versus BAC shows that a correlation between beta(60)(y) and BAC (x) has a logarithmic trend line. The value of alcohol elimination rate shows a slight increment with increase of BAC alcohol, with the mean value of beta(60) = 0.221 +/- 0.075 g/kg. Differences in values of beta(60) among consecutive intervals of Delta(BAC) = 0.1 g/kg are not significant (p > 0.05). When obtained samples were grouped into ranges of 0.5 g/kg each in these intervals beta(60) had the following values by range: 0.1-0.49 g/kg = 0.139 g/kg +/- 0.035; 0.5-0.99 g/kg = 0.184 g/kg +/- 0.043; 1-1.49 g/kg = 0.213 g/kg +/- 0.052; 1.5-1.99 g/kg = 0.239 g/kg +/- 0.058; 2-2.49 g/kg = 0.265 g/kg +/- 0.073; 2.5-2.99 g/kg = 0306 g/kg +/- 0.096. Differences in values of beta slope among consecutive intervals of Delta(BAC) = 0.5 g/kg are significant (p < 0.01). The elimination curve in the BAC interval 0.5-2.5 g/kg has a linear trend, while beta-slope (y)/BAC (x) correlation is given as beta(60) = 0.15 g/kg + (0.05 g/kg x BAC). Retrograde calculation of the blood alcohol concentration in tempore criminis (BAC(tc)) based on the determined alcohol concentration in the blood specimen (BAC(t)) shows a statistically significant difference between BAC(tc) calculated using a standard zero-order model versus corrected methodology. The higher the BAC(t) and the longer the calculation time, the greater and statistically more significant (p < 0.01) is the difference between the calculated values of BAC(tc).

Simmat-Durand L; Lejeune C; Gourarier L. Pregnancy under high-dose buprenorphine. European Journal of Obstetrics & Gynecology and Reproductive Biology 142(2): 119-123, 2009. (21 refs.)

Objective: This study was first conducted to compare the consequences of the use of methadone and high-dose buprenorphine in pregnancy in France and secondly to describe the heterogeneity of women under high-dose buprenorphine. This paper focuses on the second point only. Study design: From October 1998 to September 1999, data on pregnancy, delivery outcomes and neonatal parameters were collected for 251 addicted women on methadone or high-dose buprenorphine (HDB) substitution followed in 35 hospitals and clinics in continental France. Then the data of 159 women who had been taking HDB during pregnancy and had delivered 160 live infants were analyzed. Results: Most of these women were treated as outpatients by general practitioners. 43% of them belong to what we considered a "hidden population" of drug users: most of them were native French citizens, who lived with the future fathers in their own homes, had at least some secondary education, and were usually not followed in specialized centers for drug addicts. Almost all the women smoked every day during their pregnancies; 20% used heroin during the last 4 weeks preceding delivery; 16% admitted having injected HDB at least once. Notably. neither the severity nor the duration of the neonatal abstinence syndrome (NAS) seemed to be related to the daily doses of the substitution agent. Half of the newborns were treated for NAS, mainly with morphine hydrochloride. Conclusion: Although two different populations of women were clearly identified, 64 with no social disadvantage and 95 socially disadvantaged, there was no difference between the groups as for the severity of NAS which was only related to the mothers' compliance with a programme of treatment against addiction.

Stroud LR; Paster RL; Papandonatos GD; Niaura R; Salisbury AL; Battle C et al. Maternal smoking during pregnancy and newborn neurobehavior: Effects at 10 to 27 Days. Journal of Pediatrics 154(1): 10-16, 2009. (36 refs.)

Objective: To examine effects of maternal smoking during pregnancy on newborn neurobehavior at 10 to 27 days. Study design Participants were 56 healthy infants (28 smoking-exposed. 28 unexposed) matched on maternal social class., age, and alcohol use. Maternal smoking during pregnancy was determined by maternal interview and maternal saliva cotinine. Postnatal smoke exposure was quantified by infant saliva cotinine. Infant neurobehavior was assessed through the NICU Network Neurobehavioral Scale. Results: Smoking-exposed infants showed greater need for handling and worse self-regulation (P < .05) and trended toward greater excitability and arousal (P < .10) relative to matched, unexposed infants (all moderate effect sizes). In contrast to prior studies of days 0 to 5, no effects of smoking-exposure on signs of stress/abstinence or muscle tone emerged. In stratified, adjusted analyses, only effects on need for handling remained significant (P < .05, large effect size). Conclusions Effects of maternal smoking during pregnancy at 10 to 27 days lire subtle and consistent with increased need for external intervention and poorer self-regulation. Along with parenting deficits, these effects may represent early precursors for long-term adverse outcomes from maternal smoking during pregnancy. That signs of abstinence shown in prior studies of 0- to 5-day-old newborns did not emerge in older newborns provides further evidence for the possibility of it withdrawal process in exposed infants.

Taylor RE; Raysor BR; Kwagyan J; Ramchandani VA; Kalu N; Powell-Davis M et al. Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans. Alcoholism: Clinical and Experimental Research 32(12): 2074-2080, 2008. (36 refs.)

Malt liquor (ML) beverages have become increasingly popular among urban minority groups, due partly to their inexpensive price and targeted advertising. We hypothesized that nonfermented by-products contained in ML beverages will alter the pharmacokinetics (PK) and pharmacodynamic (PD) effects of its ethanol content. In addition, we determined the effect of alcohol dehydrogenase (ADH) genotypes on the PK following consumption of ML beverages. The study was conducted in 31 healthy adult African-American social drinkers, mean +/- SD age of 22.3 +/- 1.3 years, and weight of 70.7 +/- 10.9 kg. Participants were administered ethanol, in randomized order, 2-weeks apart, in the form of oral ML beverage (6%v/v), or isocaloric solution of diet soda-ethanol (DS-Etoh) beverage (6%v/v). During each session the beverage was consumed over 4 minutes and breath alcohol concentrations (BrAC) as well as subjective and behavioral effects of ethanol were evaluated over 180 minutes. Pharmacokinetic parameters of ethanol were calculated using Michaelis-Menten elimination kinetics. The effect of ML and ADH genotype on PK was evaluated using the Wilcoxon rank-sum test and the Wilcoxon signed rank test, respectively. Results show a slower mean rate of absorption, K-a, (0.12 vs. 0.15 min(-1), p = 0.03) and a longer time to reach maximum concentration, T-max, (28 vs. 23 minute, p < 0.01) for the ML compared with DS-Etoh beverage. The ML beverage resulted in a larger area under the BrAC-time curve compared with DS-Etoh beverage (8.4 vs. 6.8 min g/dl, p = 0.02). There was no difference in the subjective PD effects between the 2 beverages. Results show that exposure to ethanol following the consumption of ML beverages is different compared to that following nonmalt beverages in African-Americans. These differences may be related to nonfermented by-products present in commercially available ML products. These PK differences do not appear to result in significant perceived alcohol PD changes, nor are they related to ADH genotype.

Terry MB; Knight JA; Zablotska L; Wang Q; John EM; Andrulis IL et al. Alcohol metabolism, alcohol intake, and breast cancer risk: A sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Research and Treatment 106(2): 281-288, 2007. (37 refs.)

Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Verster JC. The alcohol hangover: A puzzling phenomenon. (review). Alcohol and Alcoholism 43(2): 124-126, 2008. (17 refs.)

The alcohol hangover develops when blood alcohol concentration (BAC) returns to zero and is characterized by a feeling of general misery that may last more than 24 h. It comprises a variety of symptoms including drowsiness, concentration problems, dry mouth, dizziness, gastro-intestinal complaints, sweating, nausea, hyper-excitability, and anxiety. The alcohol hangover is an intriguing issue since it is unknown why these symptoms are present after alcohol and its metabolites are eliminated from the body. Although numerous scientific papers cover the acute effects of alcohol consumption, researchers largely neglected the issue of alcohol hangover. This lack of scientific interest is remarkable, since almost everybody is familiar with the unpleasant hangover effects that may arise the day after an evening of excessive drinking, and with the ways these symptoms may affect performance of planned activities. Many people favour the (unproven) popular belief that dehydration is the main cause of alcohol hangover symptoms. More recently the potential role of the immune sytem and the cytokines is reviewed.

Wolf A; Bray GA; Popkin BM. A short history of beverages and how our body treats them. Obesity Reviews 9(2): 151-164, 2008. (77 refs.)

Numerous studies have demonstrated that beverages containing sugar, high fructose corn syrup (HFCS) or alcohol are handled differently by the body than when sugar or HFCS are incorporated in solid foods and as a result the overall caloric intake from solid food does not adjust to account for the calories in these beverages. A consideration of our evolutionary history may help to explain our poor compensatory response to calories from fluids. This paper reviews the history of eight important beverages: milk, beer, wine, tea, coffee, distilled alcoholic beverages, juice and soft drinks. We arrive at two hypotheses. First, humans may lack a physiological basis for processing carbohydrate or alcoholic calories in beverage because only breast milk and water were available for the vast majority of our evolutionary history. Alternatives to those two beverages appeared in the human diet no more than 11 000 years ago, but Homo sapiens evolved between 100,000 and 200,000 years ago. Second, carbohydrate and alcohol-containing beverages may produce an incomplete satiation sequence which prevents us from becoming satiated on these beverages.

Wurst FM; Dursteler-MacFarland KM; Auwaerter V; Ergovic S; Thon N; Yegles M et al. Assessment of alcohol use among methadone maintenance patients by direct ethanol metabolites and self-reports. Alcoholism: Clinical and Experimental Research 32(9): 1552-1557, 2008. (54 refs.)

Background: Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. Patients and Methods: A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. Results: Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were >= 8 in 15 male and > 5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (> 50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. Conclusion: (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising.

Yang SJ; Wang HY; Li XQ; Du HZ; Zheng CL; Chen HG et al. Genetic polymorphisms of ADH2 and ALDH2 association with asophageal cancer risk in southwest China. World Journal of Gastroenterology 13(43): 5760-5764, 2007. (27 refs.)

AIM: To evaluate the impact of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms on esophageal cancer risk. METHODS: One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2 genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer (PCR-CTPP) method. Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence interval (95% CI). RESULTS: Both ADH2*1 allele and ALDH2*1/*2 allele showed an increased risk of developing esophageal cancer. The adjusted OR (95% CI) for ADH2*1 allele compared with ADH2*2/*2 was 1.65 (95% CI = 1.02-2.68) and 1.67 (95% CI = 1.02-2.72) for ALDH2*1/*2 compared with ALDH2*1/*1. A significant interaction between ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83 (95% CI = 1.13-2.95). Furthermore, when compared with ADH2*2/*2 and ALDH2*1/*1 carriers, ADH2*1 and ALDH2*2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers (OR = 2.46, 95% CI = 0.98-6.14), and a significantly elevated risk of developing esophageal cancer among alcohol drinkers among alcohol drinkers (OR = 9.86, 95% CI 3.10-31.38). CONCLUSION: ADH2 and ALDH2 genotypes are associated with esophageal cancer risk. ADH2*1 allele and ALDH2*2 allele carriers have a much higher risk of developing esophageal cancer, especially among alcohol drinkers.

Yokoyama A; Tsutsumi E; Imazeki H; Suwa Y; Nakamura C; Yokoyama T. Contribution of the alcohol dehydrogenase-IB genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men. International Journal of Cancer 121(5): 1047-1054, 2007. (40 refs.)

The less-active homozygous alcohol dehydrogenase-IB (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level (Copyright 2007, Wiley-Liss

Zhang FF; Hon LF; Terry MB; Lissowska J; Morabia A; Chen JB et al. Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, Poland. International Journal of Cancer 121(9): 2060-2064, 2007. (23 refs.)

Genetic variations increasing blood levels of acetaldehyde, the first metabolite of alcohol, refrain their carriers from drinking alcohol but may also put them at increased risk of cancer because of the mutagenic and carcinogenic effect of acetaldehyde. In a population-based study of 305 cases and 428 controls in Warsaw, Poland, we evaluated the effect of polymorphisms in alcohol metabolizing genes. including ADH1B (Ex9+5C>T, Ex3+23A>G, Ex3+58A>T and Ex9+77A>G), ADH1C (EX8-56A>G and Ex6-14G>A) and ALDH2 (Ex1+82A>G), on levels of alcohol drinking and susceptibility of stomach cancer. We found that among control subjects frequency of alcohol drinking varied by alcohol metabolizing genotype. In particular, the weekly consumption of individuals carrying the AA, GA and GG genotypes of ALDH2 Ex1+82A >G polymorphism were 3.75, 2.26 and 1.53 drinks, respectively (p = 0.04). However, none of the assessed polymorphisms in these 3 genes had a measurable effect on stomach cancer risk. When stratified by ALDH2 Ex1+82A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR = 2.63, 95% CI = 1.00-6.88) and 3-fold risk (OR = 3.66, 95% CI = 1.19-11.24) among those with 40 or more drink-years. In summary, our results suggested that the ALDH2 Ex1+82 G allele may be functionally deficient in eliminating acetaldehyde and discourage alcohol drinking. Furthermore, heavy drinkers of alcohol who were genetically prone to accumulate acetaldehyde may face an increased risk of stomach cancer.

Zimatkin SM; Buben AL. Ethanol oxidation in the living brain. Alcohol and Alcoholism 42(6): 529-532, 2007. (17 refs.)

Aim: The examination of the possibility of ethanol oxidation in the brain in vivo and the evaluation of the enzyme catalase in this process. Methods: We anesthetized rats and perfused the brain with ethanol solutions through the lateral ventricle and collected the perfusate from the Cisterna magna. We determined ethanol and acetaldehyde in the perfusate by gas chromatography. Results: It was found that the passage of ethanol solution (85 and 90 mM) through the ventricular system of the rat brain (643 l/min) results in the significant (up to 98%) elimination of ethanol from the perfusing fluid and in the appearance of acetaldehyde (up-to 60 M) in the perfusate. The addition of the catalase inhibitor, aminotriazole, (10 mM) to the perfusing fluid decreased ethanol elimination significantly. Conclusions: The ethanol oxidation and AA accumulation take place in the living brain. The enzyme catalase is involved in this process.

Zimmermann-Baer U; Notzli U; Rentsch K; Bucher HU. Finnegan Neonatal Abstinence Scoring System: Normal values for first 3 days and weeks 5-6 in non-addicted infants. Addiction 105(3): 524-528, 2010. (13 refs.)

Objective: The neonatal abstinence scoring system proposed by Finnegan is used widely in neonatal units to initiate and to guide therapy in babies of opiate-dependent mothers. The purpose of this study was to assess the variability of the scores in newborns and infants not exposed to opiates during the first 3 days of life and during 3 consecutive days in weeks 5 or 6. Patients and methods: Healthy neonates born after 34 completed weeks of gestation, whose parents denied opiate consumption and gave informed consent, were included in this observational study. Infants with signs or symptoms of disease or with feeding problems were excluded. A modified scoring system was used every 8 hours during 72 hours by trained nurses; 102 neonates were observed for the first 3 days of life and 26 neonates in weeks 5-6. A meconium sample and a urine sample at weeks 5-6 were stored from all infants to be analysed for drugs when the baby scored high. Given a non-Gaussian distribution the scores were represented as percentiles. Results: During the first 3 days of life median scores remained stable at 2 but the variability increased, with the 95th percentile rising from 5.5 on day 1 to 7 on day 2. At weeks 5-6 median values were higher during daytime (50th percentile = 5, 95th percentile = 8) than night-time (50th percentile = 2, 95th percentile = 6, P = 0.02). Conclusion: Scores increase from days 1-3 to weeks 5-6 and show day-night cycles with 5-6 weeks. Values above 8 can be considered pathological. This data may help to raise suspicion of narcotic withdrawal and to guide therapy.