Alcohol and alcoholism (Oxford, Oxfordshire). Supplement最新文献

Ethanol is oxidised not only in the liver, but also in the gastrointestinal tract. Although this ethanol metabolism is less than that of the liver, it has some important relevance with respect to the first pass metabolism of alcohol and to ethanol induced tissue toxicity. In the gastrointestinal tract, ethanol can be metabolised not only in the mucosal cell via alcohol dehydrogenase (ADH) and microsomal ethanol oxidising system (MEOS), but also in a great variety of bacteria. Depending on the gastrointestinal location, one or the other metabolic pathway of alcohol may be predominant. The metabolism of ethanol by gastric ADH, the so called first pass metabolism, influences ethanol blood concentrations not only in the portal vein and thus in the liver, but also in the systemic circulation. As gastric ADH activity is decreased in younger women, in the elderly, in the alcoholic, during fasting and after treatment with certain H-2-receptor antagonists, increased blood ethanol concentrations may occur in these situations after oral intake of ethanol. However, this first pass metabolism of alcohol is influenced not only by ADH activity but also by the speed of gastric emptying (e.g. slow gastric emptying leads to increased first pass metabolism). Finally, gastric morphology also determines first pass metabolism. Chronic atrophic gastritis and Helicobacter pylori associated gastric injury lead to a decrease of gastric ADH activity, and thus possibly to a decreased first pass metabolism of alcohol. In addition, the local production of acetaldehyde from ethanol in the oesophagus, where significantly more sigma-ADH is present, may contribute to tissue injury and this may lead to the well known ethanol associated oesophageal cancer development. Various isoenzymes of ADH exist in the colorectum and they are also capable of producing acetaldehyde in amounts sufficient to injure the mucosa. Besides ADH, the MEOS, a mixed function oxidase, also metabolises ethanol. This system is inducible by chronic alcohol consumption and is involved in the metabolism of various xenobiotics including drugs and procarcinogens. Thus, an increased activation of dietary procarcinogens by this enzyme system may also contribute to carcinogenesis in the alcoholic. Finally, a great variety of gastrointestinal bacteria are capable of metabolising ethanol to acetaldehyde. This is possibly of major importance in the colorectum where faecal bacteria, especially anaerobes in the rectum, can produce high amounts of acetaldehyde, and this correlates with mucosal hyperregeneration suggesting an acetaldehyde mediated mucosal damage.

Previous studies have shown that naltrexone and ondansetron, an opiate and 5-HT3 receptor antagonist respectively, can reduce alcohol self-administration. In the present study, we have shown a synergistic interaction between naltrexone and ondansetron in reducing alcohol intake in mice and rats. Small doses of ondansetron and naltrexone which are essentially ineffective on their own, produce powerful suppression of alcohol intake when given together. Although the exact mechanisms underlying this synergistic interaction remain to be explored, the combined use of these agents might have potential clinical importance.

The clinical management of co-morbidity of psychiatric illness and substance abuse disorders (SAD) is complex. Each condition requires management in its own right. Either conjoint treatment is required or clinicians in psychiatric services must develop expertise in the management of SAD and clinicians in SAD services must develop expertise in the management of psychiatric illness. To date few serious attempts have been made for the development of integrated services in Australia. Specific clinical issues are highlighted; the principles of intervention are presented and the use of a systematic protocol is suggested.

The therapy of alcohol-related liver disease remains relatively unsatisfactory despite years of research designed to understand the pathogenesis of alcoholic liver injury and the processes involved in recovery from alcohol-related liver injury. Drugs such as the corticosteroids and colchicine appear to have a place in the management of some patients with alcohol-related liver disease but their use is not widespread in clinical practice. Liver transplantation has become an increasingly used therapy in patients with advanced liver disease but the enthusiasm of the early 1990s is now being replaced by a more cautious approach, particularly to those who have not abstained from alcohol for a significant period prior to transplant assessment. The brightest area in any discussion of treatment approaches to alcoholic liver disease is that of predicting the future. A number of agents designed to modify the inflammatory response and the endotoxaemia associated with significant alcoholic liver injury may be more beneficial than current drugs used for severe alcoholic hepatitis or cirrhosis. As in all discussions of alcohol-related liver disease and its management, it is important to highlight the need to exclude other forms of liver injury in patients who drink heavily as those diseases respond more to specific therapies than does alcoholic liver disease. The underlying therapy for all patients with alcoholic liver disease is abstinence from alcohol and the importance of encouraging patients to cease their damaging intake of alcohol can not be overemphasised.

A complex disease may be defined as a disease that has a complex phenotype, no single causal agent and a range of influencing factors, both genetic and environment. The paper considers how the aetiology of such disorders may be unravelled using recently developed genetical and statistical methods. Problems are illustrated using ischaemic heart disease, congenital neural tube defects and depression as examples.

Long-Evans Cinnamon (LEC) and Long-Evans Agouti (LEA) rats are mutant strains established from Long-Evans rats. LEC rats display hereditary hepatitis and spontaneous hepatocellular carcinoma, but LEA rats do not develop liver diseases. We previously demonstrated that LEC rats had an impairment of liver aldehyde dehydrogenase (ALDH) activities, and all LEC rats which were fed with a liquid diet containing 5% ethanol died within 2 weeks. In the present study, we also found that LEA rats could not metabolize ethanol and died after being fed the same diet. Remarkably, in the liver of LEA rats, low Km ALDH activities were suppressed as much as in LEC rats. These results suggested that both LEC and LEA rats have hereditary deficiencies in ALDH. Nucleotide sequence analysis of ALDH2 genes in both LEC and LEA rats demonstrated that the point mutation of the codon for residue 67 encoding Gln to Asp was observed; this was not so in either Long-Evans rats or Wistar rats. This mutation in ALDH2 genes may cause inactivation of ALDR activity in LEC and LEA rats.

Treatment of wild-type S49 murine lymphoma cells with 50 mM ethanol for 24 hr caused a 14% decrease in the Gs activity (an ability to compensate the deficiency of stimulatory GTP-binding regulatory protein, Gs, in membrane from CYC-S49 murine lymphoma cells) and a 29% decrease in the amount of alpha-subunit of Gs, Gs alpha. The Gs activity also decreased by treatment of the cells with methanol, propan-1-ol and butan-1-ol with an increasing efficiency according to the carbon chain length of each alcohol. A metabolite of ethanol, acetate, showed no reduction in either the Gs activity or the amount of Gs alpha. The Gs activity in membrane preparations from S49 cells was stable in a solution containing 50-250 mM ethanol or 0.01-10 mM acetaldehyde. When human erythrocytes were treated with 50 or 100 mM ethanol under the same conditions used for S49 cells, the Gs activity did not decrease but rather increased slightly, without any change in the Gs alpha content. These results indicate that the reduction in Gs activity and in Gs alpha content depends on the altered metabolism of S49 cells that can be induced by ethanol itself. Human erythrocytes lack such a responsiveness.

The ability to make use of reflective cognitive operations in monitoring and evaluating remembered events is impaired in subgroups of nominally cognitively unimpaired, detoxified alcoholics. Alcoholics, relative to controls, make more errors in identifying the source of remembered information (i.e. whether a remembered word was self-generated or was a stimulus word presented by the experimenter), and are impaired in their ability to inhibit confabulatory errors (intrusions). The cognitive-memory impairment expressed in benzodiazepine-treated normal volunteers mimics this impairment in alcoholics. Disturbances in prefrontal and frontal lobe functions may be involved in this selective impairment in cognition in many alcoholics and may also contribute to what accounts for the failures in reflective cognitive operations observed in amnestic patients.

The Wernicke-Korsakoff syndrome is a neuropathological term which encompasses two clinical syndromes in thiamine-deficient alcoholics, Wernicke's encephalopathy and Korsakoff's psychosis. Wernicke's encephalopathy is characterised by eye and gait disorders and mental confusion, and can lead to the profound and permanent amnesia known as Korsakoff's psychosis. Despite this specific difference, both conditions appear to have identical neuropathology with haemorrhages and other lesions around the ventricular system. The memory deficit has been attributed to a number of brain lesions, including a recent suggestion that brain pathways utilising particular neurotransmitters are specifically damaged. To examine this, the number of chemically identified neurons in particular brain regions was quantified in patients with Wernicke's encephalopathy alone or in combination with Korsakoff's psychosis and compared with age- and sex-matched controls. Noradrenaline, a neurotransmitter thought to be involved in the process of selective attention, is localised in pathways projecting to the cortex. Our patients with either Wernicke's encephalopathy or additional Korsakoff's psychosis do not differ from controls in the distribution and number of these cells. Serotonin is another neurotransmitter that has been linked with alcohol dependency. Both patient groups have a profound loss of serotonin-containing neurons compared with controls. The loss of forebrain neurons containing acetylcholine in patients with Alzheimer's disease has implicated this neurotransmitter in the maintenance of memory functions. There was a large variation in the number of these forebrain neurons in thiamine-deficient alcoholics compared with controls. Cholinergic cell loss reflected the severity of cognitive dysfunction, but was not exclusive to patients with amnesia. Two thalamic nuclei are involved in relaying memories for storage and retrieval, the anterior and mediodorsal thalamic nuclei. While patients with Wernicke's encephalopathy often had neuronal loss in the mediodorsal nucleus, only patients with Korsakoff's psychosis had cell loss in both medial thalamic nuclei. The results suggest that cumulative lesions contribute to the amnesia seen in thiamine-deficient alcoholics, including deficits in serotonergic, cholinergic and medial thalamic pathways.

In this paper, two of the major themes in contemporary neuropsychological research are reviewed. These are the nature of cognitive impairment observed in alcohol related brain injury, and the cause or causes of alcohol related brain injury. Two experiments are briefly reported which address these issues. The first experiment concerns the nature of abilities which are involved in a test of memory (delayed matching to sample), which is fundamental to current experimental models of human amnesia. The second experiment involves preliminary data from a randomised, double-blind, multi-dose trial of intra-muscular thiamin for the treatment of alcohol related brain injury, in alcohol dependent subjects who do not show any overt signs of Wernicke-Korsakoff syndrome.