Possible interaction between ethanol and drugs and their significance for drug therapy in the elderly]

Even though alcohol dependence is not often found in the elderly, alcohol consumption and alcohol abuse are both common. As the elderly also often take medication on a regular basis, this group is at particularly high risk for problems resulting from the concurrent use of these substances. Physical changes as a result of the aging process (e.g. reduction of body water, decrease of hepatic blood flow) and alcohol related diseases can influence the pharmacokinetics and pharmacodynamics of both ethanol as well as other drugs. Alcohol dehydrogenase (ADH), acetaldehydede hydrogenase (ALDH) and cytochrome P450 2E1 are the enzymes responsible for the metabolism of ethanol. These enzymes are also the sites of direct pharmacological interaction between ethanol and other drugs, however, altered effects of medication can also be caused by ethanol adding to or reducing the drug's effect. Although some of these effects result from heavy use of alcohol, others can also occur with moderate use. Interactions have most frequently been described for analgetics, psychopharmacologically active drugs, antihistamines, anticoagulants antihypertensive drugs and antibiotics.     

Genetics of alcohol and tobacco use in humans

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.     

Genetics of alcohol and tobacco use in humans

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.     

The contribution of genetics to addiction therapy approaches

Addictions, including alcohol dependence, which is the focus of this article, are complex genetic diseases. Recently, several individual genes that contribute to the risk for alcohol dependence have been identified, and more are expected to be in the near future. Among these are genes encoding alcohol and aldehyde dehydrogenases and GABA(A) receptor subunits. These reveal pathways of vulnerability and provide targets for rational drug design. It is likely that response to particular therapies is also a complex trait influenced by genetics, but studies to explore this are just beginning. We discuss some studies on bromocriptine, naltrexone, and serotonergic agents. Adding a genetic component to treatment trials could greatly help to understand the biological basis of variations in the efficacy of therapies and, in the future, could lead to individualized choices of therapy.     

Quantitative risk factors as indices of alcoholism susceptibility

Alcoholism is a complex disorder involving both genetic and environmental factors and interactions between them. Localizing and characterizing the genetic influences on susceptibility to alcohol dependence may provide new insights into pathology and new avenues for treatment and prevention. However, because of the complex nature of the disorder, the binary categorization of individuals as affected or unaffected may be a poor indicator of their underlying genetic susceptibility. Quantitative risk factors, or endophenotypes, that differentiate levels of severity among affected individuals and levels of susceptibility among unaffected individuals, provide one solution to this problem. Genetic studies of such quantitative risk factors in families of probands with alcohol dependence may help to disentangle the complex genetic architecture of this disorder.     

Quantitative risk factors as indices of alcoholism susceptibility

Alcoholism is a complex disorder involving both genetic and environmental factors and interactions between them. Localizing and characterizing the genetic influences on susceptibility to alcohol dependence may provide new insights into pathology and new avenues for treatment and prevention. However, because of the complex nature of the disorder, the binary categorization of individuals as affected or unaffected may be a poor indicator of their underlying genetic susceptibility. Quantitative risk factors, or endophenotypes, that differentiate levels of severity among affected individuals and levels of susceptibility among unaffected individuals, provide one solution to this problem. Genetic studies of such quantitative risk factors in families of probands with alcohol dependence may help to disentangle the complex genetic architecture of this disorder.     

Mendelian and trans-generational inheritance in hypertensive renal disease

Familial risk in hypertensive renal disease has stimulated a search for genetic variation contributing to this risk. The current phase of population genetic studies has sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success. It is also clear that narrowly defined loci and genes containing variation contributing to disease risk have been identified. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few if any variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining heritable risk may be located. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.     

Stroke: epidemiology, risk factors, and genetics

Stroke constitutes a major global challenge for health policy and healthcare economics. Reducing stroke burden requires extensive knowledge of risk factors and, if applicable, preventive control. Risk factors may be categorized in non-modifiable biological factors, such as age, gender, race/ethnicity; proatherosclerotic/prothrombotic factors (hypertension, diabetes, dyslipidaemia, other serologic and haemostasis factors); cardiac comorbidity (CAD, CHF, atrial fibrillation); lifestyle factors, which play an increasing role, e.g. smoking, physical inactivity, alcohol consumption. These traditional risk factors are extended by rapidly growing efforts in elucidating genetic backgrounds for stroke. Genetic polymorphisms of functionally or pathophysiologically important proteins are investigated in the setting of case-control-studies for their role as candidate genes. Meta-analyses have corroborated the association of the factor V-Leiden arg506gln, MTHFR-C677T, and ACE-insertion-deletion polymorphisms with stroke. Current population-based, genome-wide linkage analyses face high expectations for identifying new genetic risk factors.     

Genetic Variation Among fruit flies of the Genus Bactrocera (Diptera: Tephritidae: Dacinae)

Genetic variation in four species of fruit flies belonging to the genus Bactrocera (=Dacus) viz. B. cucurbitae, B. dorsalis, B. diversa and B. zonata was carried out using five gene?Cenzyme system, namely, aldehyde dehydrogenase, alcohol dehydrogenase, glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase (IDH) and octanol dehydrogenase. Enzyme activity was resolved at six loci in the four species. Except IDH-1, all the loci were found to be polymorphic in four species. The amount of observed and expected heterozygosity was found to be higher in B. zonata as compared to other species. Nei??s genetic identity value shows that all the four species are phylogenetically very close.     

Preclinical and clinical pharmacology of alcohol dependence

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action.     

Alcohol consumption and suicide

About 90% of people in Western countries use alcohol at some time in their lives, and 40% experience temporary or permanent alcohol-related impairment in some area of life as a result of drinking. Multiple sociocultural and environmental factors influence suicide rates, and thus studies conducted in one nation are not always applicable to other nations. Impulsivity and aggression are strongly implicated in suicidal behaviour. Constructs related to aggression and impulsivity confer additional risk for suicidal behaviour in people with alcohol dependence. Lower serotonin activity is tied to increased aggression/impulsivity, which in turn may enhance the probability of suicidal behaviour. Acute alcohol use is associated with suicide. Suicide completers have high rates of positive blood alcohol. Intoxicated people are more likely to attempt suicide using more lethal methods. Alcohol may be important in suicides among individuals with no previous psychiatric history. Alcohol dependence is an important risk factor for suicidal behaviour. Mood disorder is a more powerful risk factor for suicide among problem drinkers as age increases. All individuals with alcohol use disorders should be assessed for suicide, especially at the end of a binge or in the very early phase of withdrawal. Middle-age and older men with alcohol dependence and mood disorders are at particularly high risk.     

Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms

Alcoholism is a major public health problem and resembles, in many ways, other chronic relapsing medical conditions. At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms. Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease, particularly in genetically susceptible individuals. In contrast, long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states, and gain importance following a prolonged history of dependence. Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications, the aldehyde dehydrogenase blocker disulfiram, the opioid antagonist naltrexone (NTX) and the functional glutamate antagonist acamprosate (ACM). The treatment toolkit is likely to be expanded in the near future. This will improve overall efficacy and allow individualized treatment, ultimately taking in account the patient's genetic makeup. In a second wave, early human efficacy data are available for the 5HT3 antagonist ondansetron, the GABA-B agonist baclofen and the anticonvulsant topiramate. The third wave is comprised of compounds predicted to be effective based on a battery of animal models. Using such models, a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development. These include the cannabinoid CB1 receptor, receptors modulating glutamatergic transmission (mGluR2, 3 and 5), and receptors for stress-related neuropeptides corticotropin releasing factor (CRF), neuropeptide Y (NPY) and nociceptin. Once novel treatments are developed, the field faces a major challenge to assure their delivery to patients.     

Association of traditional risk factors with coronary calcification in persons with a family history of premature coronary heart disease: the study of the inherited risk of coronary atherosclerosis.

BACKGROUND: Genetic factors strongly influence the risk of coronary heart disease (CHD), but their contribution to variation in coronary atherosclerosis beyond that measured by traditional CHD risk factors is uncertain. METHODS: We recruited healthy subjects with family histories of premature CHD. We assessed traditional risk factors and performed electron beam tomography (EBT) to quantitate coronary artery calcification (CAC), a marker of coronary atherosclerosis. Persons with significant risk factors that included diabetes, total cholesterol >300 mg/dL, active cigarette smoking, and poorly controlled hypertension were excluded from the study. In this paper, we report on the relationship between traditional risk factors and CAC in this cohort. RESULTS: The incidence of coronary calcification was significantly higher in this cohort than in the population-based Rochester Heart Study. In our cohort, most traditional risk factors were significantly associated with CAC on univariate analysis. On the other hand, in stepwise logistical regression, age and triglycerides were the only predictors of variation in CAC in men and accounted for only 30% of the variation; in women, age, body mass index (BMI), and triglycerides were the only traditional risk factors significantly associated with CAC variation and accounted for 22.2% of CAC variance. CONCLUSIONS: In a cohort of subjects specifically selected for the characteristic of a family history of premature CHD, traditional risk factors accounted for less than one-third of the variation in CAC, and the most important predictors of CAC after age were plasma triglycerides. This supports the opinion that other inherited risk factors have important effects on the variation in coronary atherosclerosis and that the strategy of using EBT to phenotype clinically asymptomatic subjects with regard to coronary atherosclerosis may be a useful tool for identification of genes that are associated with CHD.     

Genetic determination of human essential hypertension

Recent advances in genetic determination of human essential hypertension (EHT) are discussed by reviewing the candidate genes. Candidate genes have been selected based on genetic information from classical linkage analysis (affected sib-pair analysis) or mendelian hypertension (autosomal dominant inheritance of hypertension). Most of these genes are, directly or indirectly, coupled to salt handling of the kidney, being included in the renin-angiotensin system (RAS), steroid-hormone metabolism, and renal sodium transporters. Angiotensinogen (AGT) gene in RAS was first described as a strong candidate associated with the onset of hypertension, since sib-pair linkage analysis has demonstrated the trait loci for hypertension which includes the coding region for AGT. M235T polymorphism of AGT has been studied extensively in many populations including Japanese, and the results suggest a weak, but significant linkage with hypertension. The presence (insertion [I]) or absence (deletion [D]) of 287bp in intron 16 of angiotensin converting enzyme gene has also been examined in RAS, and the results suggest D polymorphism as a risk factor for hypertension in men. Other components in RAS, such as renin, angiotensinogen II type I receptor, or kallikrein have also been studied, but the available information is still incomplete. Genetic investigations of mendelian hypertension has identified the genetic mechanisms for glucocorticoid remediable aldosteronism, apparent mineral corticoid excess, and Liddle's syndrome as chimeric gene duplications of CYP11B1 (aldosterone synthase gene) and CYP11B2 (11beta-hydroxylase gene), mutations in the gene of 11beta-hydroxysteroid dehydrogenase type 2 that catalyzes the conversion of cortisol to cortisone, and mutations in beta or gamma subunit of epithelial sodium channel (ENaC), respectively. Subsequently, genetic variants of CYP11B2 and beta or gamma subunit of ENaC have been found, suggesting the -344C polymorphism of CYP11B2, 594S variant of betaENaC, and two rare variants of gammaENaC as risk factors for EHT. In spite of the extensive research, haplotypes in individual populations remain to be elucidcated in most candidate genes. Even casual conclusions of possible linkage with EHT need to be further examined with better determinations of phenotypes, such as ambulatory and home blood pressure monitoring or identification of onset of hypertension in cohort studies.     

Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.

Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci.     

Gender Differences in Drug Therapy

Patient response to drug therapy is affected by multiple factors, including age, renal function, diet, smoking, congestive heart failure and gender. However, the data on gender differences in pharmacotherapy are limited, predominantly because women are excluded from clinical research due to the potential risks involved during pregnancy and co-existing illnesses in elderly women. Currently some information is available on gender differences in drug therapy. Differences in drug distribution and response due to different body composition as well as the effects of hormonal differences are the few that have been documented. Differences in drug metabolism due to differences in blood concentration of enzymes such as alcohol dehydrogenase has been recently described. Pharmacotherapy may also have to be altered due to differences in disease expression, like increased vasomotor tone in women. Drug efficacy has been found to be affected by gender---an example is antiplatelet therapy for stroke prevention. Finally, the side effects of drugs may differ depending on gender. Those involved in pharmacotherapy should be aware of these differences when prescribing drugs to female patients, since the majority of clinical data regarding pharmaceuticals has been derived primarily from a population of young males.     

Molecular genetics and the epidemiology of bipolar disorder

The methodologies of epidemiology and molecular genetics are complementary approaches to identifying risk factors in bipolar disorder. Genetic linkage studies have revealed several chromosomal loci likely to contain genes that increase the risk of bipolar disorder, but major uncertainties remain about the mode of inheritance of the condition and the definition of the phenotype. Epidemiological findings have contributed to both these areas and have led to new hypotheses about causation. For example, the analysis of variability of age at onset of bipolar disorder led to studies of anticipation and a possible role of dynamic DNA repeat sequence mutations. Future epidemiological studies that aim to identify risk factors for bipolar disorder at the population level will be able to measure the interactions of genome sequence variation with other risk factors in the domain of demography, childhood experiences, exposure to adversity and availability of social support.     

Pharmacogenetics of opioids

Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics and dosage requirements. Single-nucleotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Sertürner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.     

Genotyping of alcohol dehydrogenase type 2 and 3 using a two-buffer polyacrylamide gel electrophoresis system.

Genetic polymorphisms in the alcohol dehydrogenase genes, ADH2 and ADH3, have been shown to affect individual susceptibility to diseases such as alcoholism and oesophageal cancer. Although several PCR-based methods for genotyping these enzymes have been previously developed, the two-buffer polyacrylamide gel electrophoresis system has the ability to rapidly resolve all classes of point mutations within 2-3 hours instead of the conventional overnight separation. The success of this technique is partly attributable to a discontinuous two-phase buffer system and horizontal flatbed gel electrophoresis rather than conventional vertical gels. Using a modification of this system, we were able to detect all of the known polymorphisms within ADH2 exons 3 and 9 and ADH3 exon 8, as well as a rare variant within ADH2 exon 9. This method is rapid, cost-effective, and is ideal for large scale screening programmes.