Alcohol Treatment

Alcohol Free Forever

This powerful guide walks you step-by-step through exactly what you need to do to free yourself from your alcohol addiction without going through AA meetings or expensive sessions. There are three main types of relaxation techniques you can practice when you feel upset and stressed. If you practice regularly, they will become part of your lifestyle and you may find yourself habitually more relaxed as a result. Part 2 will exercise Neuro Linguistic Programming to release thoughts and a technique of progressive muscle relaxation also negative situations. Because of the mind body connection, exercises to relax the body will also flow through the mind. Much of the stress we feel is because of our resistance to certain feelings or emotions. Alcohol Free Forever is a lifesaver ebook. This guide was extremely eye-opening and the daily emails make it extremely easy to quit and to establish a routine that did not involve alcohol. Read more here...

Alcohol Free Forever Overview


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The writer presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this ebook are precise.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Pharmacotherapy Of Alcoholism

Currently, three drugs are approved in the U.S. for treatment of alcoholism disulfiram (ANTABUSE), naltrexone (revia), and acamprosate. Disulfiram has a long history of use but has fallen into disfavor because of its side effects and problems with patient adherence to therapy. Naltrexone and acamprosate were introduced more recently. The goal of these medications is to assist the patient in maintaining abstinence. Naltrexone is chemically related to the highly selective opioid-receptor antagonist naloxone (narcan) but has higher oral bioavailability and a longer duration of action. Neither drug has appreciable opioid-receptor agonist effects. These drugs were used initially in the treatment of opioid overdose and dependence because of their ability to antagonize all the actions of opioids (see Chapters 21 and 23). Animal research and clinical experience suggested that naltrexone might reduce alcohol consumption and craving this was confirmed in clinical trials. There is evidence...

Effects Of Heavy Drinking

10.1 Effects of Abstinence on the Brain Quantitative MRI and MR Spectroscopic Imaging in Chronic Alcohol Abuse (31) Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse, and there is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are still detectable in long-term abstinent alcoholics compared to active chronic drinkers. Therefore we compared 12 recovering alcoholics, who had been abstinent from alcohol for an average of 2 years, to 8 active heavily drinking subjects with similar alcohol use variables. Metabolite concentrations in whole-brain and in gray matter and white matter of brain lobes did not differ significantly between the recovering alcoholics and active drinkers. However, active heavily drinking subjects had less frontal white matter than abstinent alcoholics and less gray matter in the orbital frontal pole and postcentral gyrus....

Alcohol Abuse and Dependence

A substantial amount of evidence supports a 5-HT dysfunction in alcohol abuse and dependence. Animal studies have shown that increased 5-HT levels reduce alcohol consumption (Farren 1995). For example, Murphy et al. (1988) reported beneficial effects with fluoxetine and fluvoxamine in reducing alcohol intake in a rat model. Although results are not consistent, some clinical trials with SSRIs have reported reduced alcohol consumption in patients with and without depression, in contrast to patients treated with TCAs, which have less robust efficacy (Cornelius et al. 1997 Lejoyeux 1996). A precise mechanism for the role of SSRIs in the treatment of alcohol dependence is not understood. To date, the beneficial effect, if any, appears to be independent of antidepressant activity (Naranjo et al. 1986, 1990). More work is needed to determine the specific patient subpopulations that might benefit most from SSRIs (see Gorelick 1989). From a risk-benefit assessment, it is reassuring that...

Concomitant Sequelae of Alcoholism

Both the direct toxic action of alcohol and the accompanying nutritional deficiency, particularly of thiamine, are considered responsible for the frequent peripheral neuropathy 45 , while alcohol-induced sexual dysfunction may occur only or predominantly during intoxication 45 . Following excessive alcohol consumption, diarrhea and tremulousness are common symptoms 58 .

Screening for Alcohol Abuse

Because concomitant sequelae of alcoholism are often present in addicts an alcohol screen should be done. The Alcohol Screen is a qualitative enzymatic quick test for the detection of alcohol in saliva or urine. The Alcohol Screen is simple and fast and shows a positive result if the level is above 0.1 alcohol. The assay detects ethanol at concentrations of 0.1 or 10mg dL respectively by color change of the test pad to light greenish-grey. The green color intensifies with higher alcohol concentration in the sample. Thus, Alcohol-Screen produces a color change in the presence of alcohol in the specimen ranging from a light green-grey color at 0.1 concentrations via middle green at medium concentrations to a dark greenish-grey color at a 3.0 alcohol concentration (Figure V-15).

Alcohol Abuse

The potential utility of delta antagonists for the treatment of alcohol abuse has excited considerable interest over the last decade for at least two reasons. First, numerous studies suggest that the abuse-related effects of alcohol are mediated, at least in part, by endogenous opioid systems 114 . Second, the relatively nonselective opioid antagonist naltrexone has acknowledged clin-

Moderators Of The Depressionimmune Link

Finally, co-morbidity in depression has emerged as a major concern in biologic research in psychiatry with recent epidemiological data showing, for example, that as many as 50 of depressed patients are co-morbid for an anxiety disorder such as panic (Stein & Uhde, 1988 Murphy, Oliver, Sobol, Monson, & Leighton, 1986). Moreover, the prevalence of alcohol and tobacco dependence is high in depressed subjects (Breslau, Peterson, Schultz, Chilcoat, & Andreski, 1998 Schuckit, 1986), but few studies have examined the contribution of alcohol intake or cigarette smoking on alterations of immune function in depressed subjects despite the well-recognized effects of these substances on immune parameters. The following will consider the effects of comorbidity for anxiety and or substance dependence in the relation between depression and immunity.

Role of Pharmacotherapy

In the majority of cases, treatment of patients suffering from alcoholism starts with the termination of alcohol use and treatment of withdrawal symptoms. The general consensus is that the complicated alcohol withdrawal syndrome (severe physical withdrawal or withdrawal with seizures, alcohol hallucinosis or delirium tremens) requires pharmacological treatment. It is also agreed that adequate hydration, electrolyte compensation, thiamine substitution and monitoring of the cardiovascular parameters are required during all phases of the withdrawal syndrome. In addition to curative therapy, avoidance of seizures and reduction of the risk for delirium tremens should be considered. Benzodiazepines are the first choice in the treatment of alcohol withdrawal syndrome, delirium tremens, and seizures during withdrawal. This is based on a broad cross tolerance with alcohol, the large therapeutic window and the fast onset of effect. Benzodiazepines are sedative, hypnotic, anti-convulsive,...

Impact of Psychoactive Drugs

Effects ofmanipulat-ing most of those systems have been studied using one or more types ofalcohol preference test. Primary emphasis has been on systems implicated in ethanol's rewarding or conditioned rewarding effects and on systems thought to underlie the negative motivational effects of withdrawal (Koob and LeMoal 2008). Because space limitations preclude a detailed review of this literature, this essay focuses on psychoactive drugs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence, as well as several drugs that have been evaluated for their therapeutic potential or that are considered to be promising candidates (Heilig and Egli 2006 Tambour and Quertemont 2007 Vengeliene et al. 2008). FDA-approved drugs Currently, only four treatment drugs are approved for the treatment of alcoholism oral or extended-release naltrexone, acamprosate, and disulfiram (Swift 2007). Disulfiram (Antabuse), which...

Implications of pharmacologically altered AEA signaling

There are an overwhelming number of implications for AEA and other endocannabinoids in various physiologically and pathophysiologically relevant human states including pain (Hohmann and Suplita, 2006), appetite (Kirkham and Tucci, 2006), reproduction (Wang et al., 2006), mood and anxiety (Witkin et al., 2005), the cardiovascular system (Ashton and Smith, 2007), alcoholism (Rodriguez de Fonseca et al., 2005), spasticity (Pertwee, 2002), neurodegeneration (Battista et al., 2006), and inflammation (Ashton, 2007). In fact, these cited references are merely examples of the numerous reviews recently written on each representative topic.

Increased Incidence of Female Breast Cancer

In women, the incidence of breast cancer has increased steadily over the past few decades in a number of countries including Finland, Denmark, USA and the UK.3i.39.4o in Finland, for example, the incidence rose from 25 per 100000 in 1953 to more than 40 per 100 000 in 1980. Although improved detection may be partly responsible, the underlying upward trend is estimated as about 1 per year since 1940. A number of factors that increase breast cancer risk have been identified, including diet, calorie intake and alcohol consumption, but lifetime exposure to oestrogens (age at menarche and menopause, use of contraceptive pill, etc.) is of major importance and environmental oestrogens might contribute to overall exposure and thereby to the rising incidence of the disease.

Exceptions To The Rules

This drug is effective for treating alcoholism because of the severe reaction that occurs when it is taken with alcohol. Another interesting drug is disulfiram (Fig. 2.7), also called tetraethyl-thiuram disulfide (trade name Antabuse). This compound has an unusual dithiocarbamate functional group. One would generally be concerned about the potential for toxicity or severe side effects from such a chemical structure. However, disulfiram is used as a medication specifically because of its toxic effects. Disulfiram is administered to patients as part of the treatment for alcoholism. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage, thus causing the patient to become violently ill if even slight amounts of alcohol are ingested while disulfiram is in the bloodstream. Several species of mushroom contain very similar compounds, which also show a severe cross-reaction with alcohol.

Pharmacological Modulation

The effects of a variety of pharmacological challenges on attentional bias have been studied. Firstly, administration of small to moderate doses of alcohol seems to increase attentional bias for alcohol- and smoking-related cues in heavy drinkers and tobacco smokers, respectively (see Field and Cox 2008). Alcohol affects a variety of neuro-transmitter systems, but its direct effects are to increase

Supplementation and Mortality

All-cause mortality in a sample of the U.S. population National Health and Nutrition Examination Survey (NHANES) I participants, n 10,550 749 deaths was inversely related to vitamin C intake standardized mortality ratio as a function of the dietary vitamin C index, 0.58 95 confidence interval (CI), 0.36-0.80 (4). The vitamin C index ranged from persons consuming < 50 mg vitamin C daily to those consuming > 50 mg vitamin C daily from diet alone and those consuming > 50 mg vitamin C daily from diet plus an average of 800 mg daily from supplementation. After adjustment for age, sex, and 10 potentially confounding variables (race, history of serious disease, education, cigarette smoking, recreational exercise, alcohol consumption, energy consumed, fat, serum cholesterol, and dietary vitamin A), the inverse relationship of vitamin C intake to mortality remained strong (standardized mortality ratio, 0.62 95 CI, 0.36-0.88). This inverse relation of total mortality to vitamin C intake...

Physiological implications of modulation of nmda receptor function by ethanol

This LTP was inhibited by intraperitoneal injection of nonintoxicating doses of etha-nol (0.5 or 1.0 g kg) given prior to the LTP induction.100 Ethanol inhibition of LTP was observed not only in the hippocampus but also in other brain regions. NMDAR-dependent LTP in the dorsomedial striatum101 was recently reported to be abolished by ethanol at concentrations as low as 10 mM.20 LTP in the dorsolateral bed nucleus was also shown to be inhibited by ethanol.102 LTP is a cellular model of learning and memory4103, and in humans, ethanol disrupts performance on a variety of short-term memory tasks104-106 and ethanol inhibition of LTP may be associated with drinking-induced blackouts.107 Finally, ethanol inhibition of LTP in the hippocampus may underlie episodes of amnesia after alcohol binge drinking.108

Associated with ethanol exposure

As mentioned above, ethanol withdrawal syndrome is a life-threatening condition and is also a hallmark for physical dependence to ethanol.122 Other symptoms of eth-anol withdrawal syndromes in humans include tachycardia, sweating, tremor, hypertension, anxiety, agitation, auditory and visual hallucinations, and confusion.121122 Therefore, ethanol withdrawal symptoms are disabling enough to lead many subjects to resume alcohol consumption at the early stages of withdrawal.2112137138 4.6 MODULATORS OF NMDA RECEPTOR FuNCTIoN AND TREATMENT oF ALCoHoL ABusE AND DEPENDENCE During the past 20 years, NMDAR antagonists have been assessed for their potential use as medication for the treatment of various CNS related disorders such as stroke, pain, and Alzheimer's disease.139,140 Several NMDAR antagonists have been tested in human trials as potential drugs that alleviate adverse phenotypes that are associated with alcoholics. For example, administration of the NMDAR antagonist, ketamine, to...

Radiation Biology And Cancer

The association between radiation exposure and the development of cancer is mostly based on populations exposed to relatively high levels of ionizing radiation (e.g., Japanese atomic bomb survivors and recipients of selected diagnostic or therapeutic medical procedures where radiation represents the major anticancer modality in terms of successful tumor care and patient survival) (Abrahamse, 2003). Those cancers that may develop as a result of radiation exposure are indistinguishable from those that occur naturally or as a result of exposure to other chemical carcinogens. Chemical and physical hazards and lifestyle factors (e.g., smoking, alcohol consumption, and diet) contribute to many of these same diseases. Cancers associated with high-dose exposure include leukemia, breast, bladder, colon, liver, lung, esophagus, ovarian, multiple myeloma, and stomach cancers. Radiation biology focuses on the understanding of the physical, biological, and chemical mechanisms of the interaction of...

Hints Of Phenotypes For Variant Sert Alleles From Genetic Studies In Mouse And

Although functional coding variants have yet to be identified in hSERTs, functional variants in promoter and intronic regions have been investigated for their relationship to clinical syndromes. As noted above, the s alleles of the 5HTTLPR have been found to associate with reduced transcriptional activity of the SERT promoter and with neuroticism and anxiety traits (Lesch et al., 1996). However, the degree to which the 5-HTTLPR influences SERT expression is at present controversial, with both supportive (Little et al., 1998 Heinz et al., 2000) and contradictory (Willeit et al., 2001) evidence. Recently, Du and co-workers (Du et al., 2000) were able to replicate the finding of Lesch of an association between 5-HTTLPR s alleles and neuroticism, but only in a male population, the gender of the original Lesch studies. These findings suggest that gender-specific expression of phenotypes may need to be considered in evaluation of SERT variants and that neuroti-cism and anxiety continue to...

Miscellaneous Medical Uses For Antipsychotic Drugs

Many antipsychotic agents can prevent vomiting due to specific etiologies when given in relatively low, nonsedative doses (see Chapter 37). Antipsychotic drugs are useful in the management of several syndromes with psychiatric features that also are characterized by movement disorders (e.g., Tourette's syndrome and Huntington's disease). Haloperidol currently is regarded as a drug of choice for these conditions, although it probably is not unique in its antidyskinetic actions. Pimozide also is used clonidine and tricyclic antidepressants (e.g., nortriptyline) also may be effective in Tourette's syndrome. Antipsychotic drugs are not useful in the management of withdrawal from opioids, and their use in the management of withdrawal from barbiturates, other sedatives, or alcohol is contraindicated because of the high risk of seizures. These drugs can be used safely and effectively in psychoses associated with chronic alcoholism especially the syndrome known as alcoholic hallucinosis.

Pharmacology And Toxicology Of Ethanol

The two-carbon alcohol ethanol, CH3CH2OH, is a CNS depressant that is widely available to adults its use is legal and accepted in many societies, and its abuse is a societal problem. The relevant pharmacological properties of ethanol include effects on the gastrointestinal (GI), cardiovascular, and central nervous systems (CNS), effects on disease processes, and effects on prenatal development. Ethanol disturbs the fine balance between excitatory and inhibitory influences in the brain, producing disinhibition, ataxia, and sedation. Tolerance to ethanol develops after chronic use, and physical dependence is demonstrated on alcohol withdrawal (see Chapter 23). Understanding the cellular and molecular mechanisms of these myriad effects of ethanol in vivo requires an integration of knowledge from multiple biomedical sciences (the terms ethanol and alcohol are used interchangeably in this chapter). Compared with other drugs, surprisingly large amounts of alcohol are required for...

Acute Ethanol Intoxication

The characteristic signs and symptoms of alcohol intoxication are well known. Nevertheless, an erroneous diagnosis of drunkenness may occur with patients who appear inebriated but who have not ingested ethanol. Diabetic coma, for example, may be mistaken for severe alcoholic intoxication. Drug intoxication, cardiovascular accidents, and skull fractures also may be confused with alcohol intoxication. The odor of the breath of a person who has consumed ethanol is due not to ethanol vapor but to impurities in alcoholic beverages. Breath odor in a case of suspected intoxication can be misleading because there can be other causes of breath odor similar to that after alcohol consumption. BALs are necessary to confirm the presence or absence of alcohol intoxication.

Alcohol Dehydrogenase

Alcohol dehydrogenase is much larger than lysozyme. It is an enzyme that can break down alcohol molecules. As such, it is the body's first defense line against alcohol molecules that are toxic for the body and can damage the nervous system. High levels of alcohol dehydrogenase are present in the body to detoxify alcohol. The enzyme does this by converting the alcohol into nontoxic molecules, such as acetate, that are easily used by cells. In this way, a dangerous molecule (alcohol) is converted by alcohol dehydro-genase into harmless foodstuff for the body. The human body has at least nine different types of alcohol dehydrogenase enzymes, each slightly different. Most of these are found in the liver and others in the lining of the stomach. Each enzyme is composed of two chains, and the different dehydrogenases can exchange their chains to create mixed enzymes that are still active. Alcohol is not the only target of these enzymes they also make important modifications to steroids and...

Congenital Disorders Of Glycosylation

The diagnosis of CDG is based on a combination of clinical symptoms and biochemical tests, the latter including the presence of a defective glycosylation pattern of glycoproteins and enzymatic assays.5,32,33 Confirmation and subtyping of CDG are established by molecular identification of the underlying genetic defects (i.e. detection of specific mutations). If CDG is suspected, initial diagnosis is currently based on the identification of alterations of the N-linked glycosylation of serum transferrin. Transferrin is a very convenient marker for this purpose, partly because of its relative abundance in serum, and also because assays for transferrin microheterogeneity are routinely available (i.e. the CDT assays for detection of alcohol misuse).

Analytical Methods For Transferrin Microheterogeneity

Over the years, many different methods for carbohydrate-modified transferrin have been used for the routine determination of CDT. This has sometimes created confusion, related to discrepancies between methods (e.g. test values are given in various absolute and relative amounts), and also their ability to distinguish between normal and elevated values (i.e. the sensitivity and specificity for heavy alcohol consumption). For example, a very high total transferrin concentration might render falsely high results, when expressing the CDT content as an absolute amount and not in relation to total transferrin.21'34'35 Moreover, changes in the definition of the analyte (e.g. heterogeneous mixtures of the asialo-, monosialo-, disialo-, and or trisialotransferrin glycoforms in the 'CDT' fraction)2,21,36 and the lack of traceability of reference intervals have hampered the clinical implementation and acceptance of this laboratory test.

Chromatographic Methods For

HPLC measurement of CDT is routinely used in hospital and research laboratories as a way to detect chronic alcohol misuse. The first HPLC method for the quantification of iron-saturated transferrin glycoforms was introduced in 1993,12 and was based on anion-exchange chromatographic separation of the different glycoforms by salt gradient elution followed by photometric detection. Since then, several variations of the original method have been published7'44-48 and a number of commercial HPLC assays for CDT have been introduced.

Therapy Of Hypertension

PRINCIPLES OF ANTIHYPERTENSIVE THERAPY Nonpharmacological therapy is an important component of treatment of all patients with hypertension. In some stage 1 hypertensives, blood pressure may be adequately controlled by a combination of weight loss (in overweight individuals), restricting sodium intake, increasing aerobic exercise, and moderating alcohol consumption. These lifestyle changes may also facilitate pharmacological control of blood pressure.

Observational studies of fruit and vegetable intake

A number of studies of people who eat a diet rich in fruit and vegetables, and therefore rich in antioxidant nutrients, have tried to test the hypothesis that fruit and vegetables lower the risk of CHD (Phillips et al., 1980 Chang-Claude et al., 1992 Thorogood et al., 1994 Key et al., 1996). In general, observational studies of vegetarians and those with diets rich in fruits and vegetables support the hypothesis that such diets might lower the risk of CHD. Vegetarians generally have high intakes of cereals, nuts and vegetable oils, carrots and green vegetables as well as fruit. However, vegetarians differ from the rest of the population in a number of important ways they tend to smoke less, have a lower body mass index and alcohol intake, and come predominantly from higher social classes, all of which are known to confer a health advantage.

Cardiovascular health

Lipids are transported as lipoproteins in the blood. These include very low-density lipoprotein-cholesterol (VLDL-C), LDL-C and high-density lipoprotein-cholesterol (HDL-C). LDL-C is removed from the circulation by binding with both plasma membranes and HDL-C, and is a less concentrated form of cholesterol. An increased level of LDL-C can result from a deficiency in the binding mechanism and is known as type II hypercholesterolaemia. This can be due to a genetic defect (familial hypercholesterolaemia) or multifactorial due to genetics, diet and lifestyle. As well as primary hypercholesterolaemia, increased cholesterol levels may be secondary to diabetes mellitus, hypothy-roidism, pregnancy, renal failure, obesity, a high alcohol intake, poor diet and various drugs, such as beta-blockers, diuretics and oral contraceptives. Hypercholesterolaemia is known to be an important risk factor in the development of atherosclerosis and CHD, and studies have shown that a 1 decrease in serum...

Correlations Between Naa And Fdgpet

This was the first clinical study of the effects of HIV infection and its progression on brain metabolites using short-TE multi-slice 1H MRSI. Figure 5 shows a representative slice of a multislice 1H MRSI experiment at TE 25ms from a control. Metabolite images of mI, Cho, Cr, and NAA were generated using the automatic fitting program developed in this lab. The raw (solid line) and fitted (dashed) 1H MR spectrum was selected from a region in white matter. We co-registered MRSI to segmented MRI data, determined atrophy-corrected absolute metabolite concentrations in major brain regions, and analyzed by region and tissue type, using linear regression in a mixed effects model. All statistical analyses used a 2x2 ANOVA (with age as a covariate when appropriate), yielding main effects of HIV infection and heavy drinking, HIV-by-alcohol interactions and group contrasts. Statistical analyses were also done for HIV+ individuals on or off highly active antiretroviral treatment (HAART) and for...

Central and Physical Effects of Hypercortisolaemia

A well-established effect of high levels of cortisol is hippocampal shrinkage 35 . Compared to healthy controls both first-episode and patients with chronic schizophrenia have reduced hippocampal volumes as demonstrated by imaging and neuro-pathological studies 36, 37 . Such structural changes are associated with functional deficits in memory (verbal) and executive function 38 . The exact etiology of hippocampal volume reduction remains unclear but is attributed to both genetic and environmental factors such as, prenatal exposure to maternal stress, iatrogenic gluco-corticoid administration, illicit drug usage and alcohol abuse and perinatal complications 39, 40 .

Molecular Mechanisms Bystanders or Actors

HSP70 has been already shown to exert antiinflammatory functions 151 , by inhibiting leukocyte adhesion and recruitment 152 or by decreasing NF-kB activation and the number of activated macrophages in a model of brain inflammation of mice overexpressing HSP70 119 . Other approaches, such as the induction of HSPs by low dose alcohol consumption, have been proposed. The authors suggested that the cardioprotective effect showed in rats was mediated by increased HSP levels, namely HSP70 and HSP32 153 .

Homocysteine And Dementia

Recent evidence suggests an association between several specific nutrient excesses and deficiencies and AD, including alcohol abuse, vitamin B12 and folate deficiency and elevated total homocysteine levels. The exact nature and significance of this association remains uncertain. Three possible explanations exist for this association

Vascular system and atherosclerosis

The rate-limiting step in PUFA biosynthesis is A-6 desaturation of a-linolenic acid and linoleic acid. Inhibition of A-6 desaturation was observed to correlate with high plasma cholesterol level 16 , high-intake of saturated fatty acids, aging 17 , male gender 18 , diabetes 19 , smoking 20 , very high alcohol intake 21 and coronary artery disease. On the other hand, intake of PUFAs may reduce total cholesterol level.

Balance of activation and deactivation

Whatever alters this balance of activation deactivation will have a very profound effect on the toxicity of a compound. For example, if the activity of a cytochrome P450 enzyme that functions as the major catalyst of the bioactivation of a chemical is elevated, then increased production of reactive intermediates will lead to enhanced toxicity. An established clinical fact is that chronic alcoholics are susceptible to the hepatotoxicity of paracetamol these people display symptoms of liver disease even when they consume therapeutic doses of the drug.17,18 As already discussed (see previous text), paracetamol is largely metabolized by conjugation with sulfate and gluc-uronic acid, and these are the principal pathways of its elimination (Figure 19.1). To a minor extent, it undergoes cytochrome P450-catalyzed oxidation to generate the quinoneimine, an electrophile that can interact with hepatic proteins to precipitate hepatotoxicity (Figure 19.3). However, the body protects itself by...

Neurotransmitter Systems Involved In Alcohol Central Effects

Neurotransmitter systems involved in alcohol dependence include pathways triggered by the excitatory amino-acid glutamate, the inhibitory neurotransmitter GABA, the monoaminergic neurotransmitters dopamine, serotonine, noradrenaline as well as endogenous opioids, anandamide and other neuropeptides (Nevo and Hamon 1995). Acute alcohol intake leads to inhibition of glutamatergic activity (Tsai und Coyle 1998, Spanagel and Bienkowski 2002), which is mediated by different biochemical mechanisms (Nie et al., 1994). Alcohol inhibits NMDA-receptor signalling by interacting with a glycine binding site with this receptor (Mihic et al., 1997, Mascia et al., 2000). Voltage-clamp experiments in hippocampal neurons revealed, that a concentration of 50 mM of ethanol is sufficient to reduce NMDA-activated currents by 60 (Lovinger et al., 1989). Additionally, glutamatergic signalling is reduced by an inhibitory input of GABA, which is activated upon acute alcohol intake (Spanagel and Bienkowski,...

5ht Receptor Subtypes

Present in highest concentration in the globus pallidus, as well as in caudate, putamen, nucleus accumbens, and hippocampal formation, with lower levels in the neocortical regions. 5-HT1B receptors act as terminal autoreceptors or heteroreceptors, modulating the release of 5-HT and other transmitters such as glutamate and acethylcholine. The knockout mouse lacking the 5-HT1B receptors displays enhanced impulsive aggressive behavior28 and vulnerability to develop alcoholism.29 In addition, recent electrophysiological studies revealed that regulation of 5-HT1B receptors plays a key role in the delayed therapeutic response to SSRIs, further establishing the importance of this receptor in mood disorders.30 5-HT1E and 5-HT1F are closely related receptors. 5-HT1E is localized in the cortex, caudate, putamen, and amygdala. 5-HT1F is located on the pyramidal cells of the cortex, in the hippocampus, and the dorsal raphe. No selective ligands are available for these two receptors, and their...

Treatment Of Alcoholdependence

The -opioid receptor antagonist Naltrexone and Acamprosate, which interacts primarily with the glutamatergic system, are the two most commonly used drugs for secondary relapse prevention in alcohol dependence in Europe. A number of double blind studies conducted during the last decade have shown that both, Naltrexone and Acamprosate prevent relapse in a relevant portion of patients - but not in all (Garbutt et al., 1999, Berglund et al., 2003). The results of recent meta-analyses suggest that the number of patients needed to treat in order to prevent one additional relapse of alcohol is about 7.5 for Acamprosate (Mann et al., 2004). This ratio points towards the need to identify predictors for response to pharmacological relapse prevention. Pharmacogenetic research may be useful in attaining this goal. Whereas for Acamprosate no pharmacogenetic analyses have been preformed, a recent study describes a dramatic improvement in treatment success for a specific genotype of a genetic...

First observation of recovery of consciousness in hepatic coma

A 50-year-old female was admitted with a history of alcohol abuse, onset of jaundice, fatigue, nausea, vomiting, and dark urine. There was no history of contact with hepatitis or of intravenous or intramuscular medication. On admission, she had spider nevi and ascites. The diagnosis was acute alcoholic hepatitis. Her condition deteriorated after admission and she became comatose and unresponsive. After remaining comatose for two days, her condition was considered as terminal and with the insistence of her relatives she was referred by her physician to me for possible hemoperfusion since nothing else could be done. One hour after hemoperfusion, she started to regain consciousness and began to recognize her relative and answer questions in sentences. Hemoperfusion was carried out for a total of 80 min. She remained conscious for about an hour after the end of the hemoperfusion, but lapsed into coma again. Three days later she was still comatose, and a second hemoperfusion was initiated....

Regulation of mtDNA Expression

MtDNA expression following chronic alcohol consumption (Enriquez et al., 1992) currently remain unknown. Thus, as shown in the previous three paragraphs, investigations from multiple laboratories have demonstrated a series of modulators that can increase or modulate mtDNA expression at both transcriptional and post-transcriptional levels. These studies have greatly aided our understanding of the regulation of mtDNA expression and replication under normal, physiological, and some pathophysiological conditions, such as alcoholism and transformation. What is less well understood, however, is what happens under other conditions in which cells are stressed. In particular, the well-accepted interaction between oxidative stress and mitochondrial dysfunction, and the implied threat to mtDNA, led us to begin to test whether mtDNA transcription was sensitive to oxidative stress.

Physiology and disease relevance

The dopaminergic system has been the focus of much research over the past 40 years because several pathological conditions such as Parkinson's disease, schizophrenia, bipolar disorder, manic depression, Tourette's syndrome, and hyperprolactinaemia are believed to be associated with either dopaminergic system dysfunction or side effect profiles of drugs used to treat these disorders. Extensive work has also been performed to analyse the genetic relationship between dopamine receptors and the diseases mentioned above (reviewed in Missale et al. 1998). However, the results that have been produced are equivocal. Thus no linkage of D2 and D4 receptors to bipolar disorder has been found (Missale et al. 1998) and the association between the dopamine D2 receptor gene and susceptibility to alcoholism is controversial (Missale et al. 1998). More recently, some evidence has been reported for the genetic association of dopamine D4 receptor polymorphisms with behavioural disorders such as...

Distribution And Pharmacokinetics Of Ghb Gbl And 14bd

The distribution of GHB into the CSF appears to lag behind that in blood or brain. After a 500 mg kg-1 intravenous dose of GHB had been administered to dogs, the plasma concentration peaked within 5 min and the brain concentration peaked within 10 min, but it was 170 min before CSF concentrations reached their maximum (Shumate and Snead, 1979). This suggests a passive diffusion of GHB from serum or brain into the CSF. In alcohol-dependent patients GHB did not accumulate in the body on repeated doses nor did it exhibit any protein binding. The mean peak plasma concentrations of therapeutic oral doses of 25 and 50mgkg-1 of GHB per day given to 50 alcohol withdrawal syndrome patients were 55 mg mL-1 (range 24-88) and 90 mg mL-1 (range 51-158), respectively (Snead et al., 1976 Ferrara et al., 1993).

Project Title Acute Drug Withdrawal In A General Medical Setting

Summary This is a proposal for a Mentored Clinical Scientist Development Award to provide supervised experience in clinical research, didactic education, and some clinical activities. This will provide a foundation for a career in academic medicine with opportunities for research, teaching, and some clinical practice. This award will allow the candidate to begin research in substance abuse treatment and Health Services Research (HSR) in a supervised setting. The effects of symptom-triggered therapy versus scheduled dosing for acute withdrawal from alcohol will be studied in a general medical population. The first two years of the award period will be spent taking graduate courses in biostatistics, pharmacology, research design and methodology, attending seminars on HSR topics, and refining the final study protocol by doing a pilot study. Practical clinical experience will be gained in outpatient clinics including rotation through community programs such as a local methadone...

The Alcohol Addictive Patient

A positive response to two or more questions indicates a strong potential for alcohol abuse. Clinicians should use this tool in conjunction with laboratory tests and a brief questionnaire that directly inquires about problems related to alcohol use 42, 48 . The National Institute of Alcohol Addiction and Abuse recommend use of the CAGE questionnaire for possible alcohol problems. Clinicians should then ask the quantity and frequency questions of all patients who drink alcohol 51, 52 . If two of four questions are positive, diagnosis of a history of alcohol abuse or dependency has a sensitivity of 74 and a specificity of 91 An optimal marker of excessive alcohol consumption has not been found. Although -yGT is the most widely used test as a marker, however, elevated levels are also caused by nonalcoholic liver disease, most hepatobiliary disorders, obesity, diabetes mellitus, hypertriglyceridemia, and the use of liver microsome-inducing drugs 55 . Also, elevated Mean Corpuscular Volume...

Liver Cirrhosis or Fibrosis

Liver cirrhosis is among the top 10 causes of death in the Western world. The disease occurs after chronic damage to hepatic cells, mainly hepatocytes, which can be caused by viral hepatitis, chronic alcohol abuse or toxic injury, biliary disease, and metabolic liver disorders 64 . Liver cirrhosis is characterized by an abnormal deposition of connective tissue in the liver, which hampers the normal functions of the liver. Other features of the disease are general tissue damage, chronic inflammation, and the conversion of normal liver architecture into structurally abnormal nodules. Secondary to these anatomical changes are disturbances in the liver function and in the hemodynamics leading to portal hypertension and intrahepatic shunting 39, 64, 103 .

Cytotoxic And Immunosuppressant Drugs

Potential risk for hepatic fibrosis, such as a history of alcohol abuse or infection with hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug. Pregnancy and lactation are absolute contraindications to methotrexate use.

The Most Common Signs of Alcohol Addiction

Alcohol consumption and abuse can have a variety of cutaneous manifestations, including palmar erythema and spider angioma (also known as spider telangiec-tasis, arterial spider, spider nevus, or nevus araneus) 57 . Alcohol can also induce diseases disease states with dermatologic manifestations 57 . Many endocrine changes are seen in patients with chronic alcoholism. Signs of hypogonadism and hyperestrogenism are seen in male patients. Hypogonadism is manifested by loss of libido and potency, testicular atrophy, reduced fertility, and reduced facial hair growth 57 . Gynecomastia, vascular spiders, changes in fat distribution, loss of body hair, and change of pubic hair to a female distribution 57 manifest hyperestrogenism. In contrast, female patients with alcoholism rarely manifest signs of masculinization. They may demonstrate breast atrophy or menstrual irregularities 57 . In 30 of patients with alcoholic hepatitis, the liver is enlarged, smooth, and occasionally tender 45 . In...

Genetically Modified Animals

Several knockout mouse models suggest a relationship between 5-HT and epilepsy. The audiogenic seizures syndrome is the first known defect caused by genetic manipulation of a 5-HT receptor subtype this provides a robust model for examination of serotonergic mechanism in epilepsy. Mutant mice lacking the 5-HT2C receptor subtype are extremely susceptible to audiogenic seizures and are prone to spontaneous death from seizures, suggesting that serotonergic neurotransmission, mediated by 5-HT2C receptors, suppresses neuronal network hyperexcit-ability and seizure activity (Brennan et al. 1997 Tecott et al. 1995 Applagate and Tecott 1998). Fehr et al. (2002) developed a congenic strain that possesses a segment of chromosome 4 from the C57BL 6 J(B6) donor strain superimposed on a genetic background estimated to be > 99 from the DBA 2 J (D2) mouse strain. The introduced segment spans the Mpdz gene. Mpdz encodes the multi-PDZ domain protein (MPDZ). Multi-PDZ domain protein's interaction with...

Psychoactive substance use

There is a higher rate of alcohol and analgesic misuse in patients with chronic pain. Between 12 and 28 percent of patients attending specialized pain clinic facilities reach the criterion for diagnosis under this category.12 High average alcohol consumption before developing a chronic painful state was found to be a poor prognostic sign in a large follow-up study of patients with lower limb pain.72 Despite these findings of an increased prevalence of substance misuse generally, there has been a change in attitude about the use of opioid medication for patients with chronic nonmalignant pain. Although it has been argued that long-term opioid use leads to increased drug dependency and further functional impairment in patients who have disproportionate pain and disability,73 recent work has not found clear evidence that this is the

Screening instruments for addiction

If the patient has a current diagnosis of addiction, this may need to be managed separately (by appropriately trained professionals) in parallel with ongoing pain management. Additionally, a past or current history of an addiction problem is a significant predictor of likelihood of running into problems when prescribing controlled substances for pain. A number of tools are available to screen for the presence of an addictive disorder. The CAGE questionnaire was developed to screen for alcohol misuse and has been adapted to screen for other drug use.38 The questionnaire is simple to administer and has been demonstrated to be both sensitive and specific as a screening tool. The Screening Tool for Addiction Risk (STAR) questionnaire is a validated tool that has been developed to evaluate addiction problems in chronic pain patients and includes questions regarding prior treatment in a drug or alcohol rehabilitation facility, as well as questions regarding nicotine use and treatment in...

Ethnicity As A Starting Point For Pharmacogenetic Investigation

Another example concerns ethnic differences in response to alcohol. Screening of various populations indicates that an alcohol dehydrogenase (ALDH2) deficiency occurs at varying frequencies (8-45 ) in populations of Mongoloid origin but is not found in Caucasian or Negroid populations. Facial flushing, an acute vasomotor dilation in response to ethanol, has attracted attention by its association with variant forms of ALDH2. Among Japanese, homozygotes and most heterozygotes for the atypical (''Asian'') ALDH2 are flushers, while those homozygous for the usual ALDH2 are nonflushers. Nearly 86 of Japanese subjects who always experienced facial flushing have inactive ALDH2, whereas infrequent flushing or an absence of flushing is associated with active ALDH2.64 As a consequence of the aversive vascular effects of ethanol, Japanese men and women with the ''Asian'' form of ALDH2 drink significantly less alcohol than those with the ''Caucasian'' form, and are more highly protected from...

Clinical Relevance of Glycine 431 Hyperekplexia

Apart from the CNS, glycine has been reported to have immunomodulatory properties, and clinical application of glycine has been attempted in a wide range of disorders, including ischemic stroke and effects of alcoholism. In most reports the results were promising but not systematically investigated (Gundersen et al., 2005).

Pharmacological Properties History

Alcohol exerts a number of effects, ranging from stimulant and pleasurable to sedative, anxiolytic, attention reduction, amnestic, anticonvulsant, muscle relaxant, hypnotic anesthetic, and can lead to death. The effects of alcohol are biphasic at low blood alcohol concentrations (BAC) it is disinhibitory, thereby facilitating spontaneous behavior and having stimulant properties, while its effects at high BAC are sedative-hypnotic (Table 1). Acute alcohol poisoning (BAC > 40 ) may result in death due to the formation of edema (swelling) in the base of the brain (medulla), where centers of respiratory and cardiovascular regulation are located. Behavioral reaction to alcohol intake depends upon several factors, including the rate of alcohol absorption, alcohol metabolism, and tolerance.

Carbohydratedeficient Transferrin

The abnormal glycoform pattern of serum transferrin that occurs as a result of prolonged heavy alcohol consumption, CDT, has emerged as a useful biochemical marker for identifying persons chronically abusing alcohol and for monitoring abstinence from alcohol during treatment.4,9 Regular high alcohol intake averaging at least 50-80 g of ethanol per day for two or more weeks typically results in an altered transferrin glycoform profile. The biological mechanism by which alcohol causes changes in the carbohydrate composition of the molecule has not yet been conclusively identified, but likely involves interferences with the systems responsible for glycosyl transfer.4,10,11 When drinking is discontinued, the glycoform pattern of serum transferrin slowly normalizes with a half-life of 1.5-2 weeks,4,12 and the time to reach a stable baseline level may require abstinence for 1 month or longer.13 The major benefit of CDT compared with other laboratory tests used in routine clinical medicine...

Interactions With Other Drugs

Li+ sometimes is used as an alternative or adjunct to antidepressants in severe, especially melancholic, recurrent depression, as a supplement to antidepressant treatment in acute major depression, including in patients who present clinically with only mild mood elevations or hypomania (bipolar II disorder), or as an adjunct when later response to an antidepressant alone is unsatisfactory. In major affective disorders, Li+ has stronger evidence of reduction of suicide risk than any other treatment. Clinical experience also suggests the utility of Li+ in the management of childhood disorders that are marked by adult-like manic depression or by severe changes in mood and behavior, which are probable precursors to bipolar disorder in adults. Evidence of efficacy of Li+ in many additional episodic disorders (e.g., premenstrual dysphoria, episodic alcohol abuse, and episodic violence) is unconvincing.

Clinical Uses Of Ethanol

The use of alcohol to treat patients in alcohol withdrawal or obstetrical patients with premature contractions is no longer recommended. Some medical centers continue to use alcohol to prevent or reduce the risk of alcohol withdrawal in postoperative patients, but administering a combination of a benzodiazepine with haloperidol or clonidine may be more appropriate. Physical dependence is demonstrated by the elicitation of a withdrawal syndrome when alcohol consumption is terminated. The symptoms and severity are determined by the amount and duration of alcohol consumption and include sleep disruption, autonomic nervous system (sympathetic) activation, tremors, and in severe cases, seizures. In addition, two or more days after withdrawal, some individuals experience delirium tremens, characterized by hallucinations, delirium, fever, and tachycardia. Delirium tremens can be fatal. Another aspect of dependence is craving and drug-seeking behavior, often termed psychological dependence....

Pregnancy and Lactation

Newborns of women with depression have been shown to have a disproportionately higher risk of lower birth weight, preterm delivery, and small size for gestational age (Steer et al. 1992). Additionally, women with depression have higher rates of smoking and alcohol consumption, which represent further risks to pregnancy outcome (Zuckerman et al. 1989). Laboratory animal studies have demonstrated no significant effects of paroxetine in offspring of exposed pregnant mice in terms of early developmental tasks, locomotor and exploratory behavior, or cognition (Christensen et al. 2000 Coleman et al. 1999). In human studies, placental passage of paroxetine from mothers to developing infants was assessed by comparing maternal serum SRI concentrations with those found in cord blood at the time of delivery (Hendrick et al. 2003b). Paroxetine and sertraline had lower ratios of umbilical cord-maternal serum drug concentrations compared with citalopram and fluoxetine. Furthermore, unlike...

Therapeutic Potential of 5HT2C Receptor Drugs for Reward Related Behavioral Problems

There are some reports of serotonergic drugs that may affect weight gain in obese individuals, acting to reduce addictive behaviors, although in each case effect size is modest. For example, some reports document a short-term benefit of fluox-etine and sertraline during the first few weeks of a smoking cessation trial and similar trends in alcohol dependence trials (Covey et al. 2002 Hitsman et al. 1999 Niaura et al. 2002 Cornelius et al. 1999 Naranjo and Knoke 2001 Naranjo et al. 1992). In general however, medications such as SSRIs have not proven to be consistently effective in treating drug abuse and dependence (Walsh and Cunningham 1997). These nonselective serotonergic drugs enhance brain 5-HT function in an indiscriminate fashion, such that 5-HT neurotransmission is increased through all of the various receptor subtypes. This may not always be desirable since different 5-HT receptor subtypes may act in an opposing fashion to modulate neuronal activity and behavioral output. For...

Human Serotonin Transporter Sert 5HTT SLC6A4 41 5HTT Cloning and Gene Organization

Victims (129). 5-HT neurotransmission has also been associated with alcohol consumption. Increased 5-HT transmission has been associated with decreased alcohol self-administration, and 5-HT uptake into platelets was found to be increased in former alcoholics (130,131). Animal stuies have shown an inverse relationship between levels of 5-HT and aggressive behavior. It has been suggested that 5-HT is involved in aggressive, impulsive behavior that may be present across a broad spectrum of psychiatric disorders, such as violent suicide (131a). Reductions of 5-HIAA in brain stem and cerebrospinal fluid and SERT binding sites in several brain regions of suicides or attempted suicides have been reported (131a). Overall, this evidence provides a good rationale for studies of the relationship of 5-HTT gene polymorphisms to psychiatric disorders.

The Scope Of Pharmacogenetics

The development of pharmacogenetics from 1950 to 2000 is charted in Table 2.1. Xenobiotic targets relevant to pharmacogenetics include drug-metabolizing enzymes, non-drug-metabolizing enzymes, receptors, ion channels, and other proteins, some of whose functions may be unknown or not well defined. Human sensitivities to nutritional and dietary components, occupational pollutants, or industrial chemicals, and to personal life-style habits such as smoking or drinking alcohol, may also be hallmarks of pharmacogenetic phenomena. Historically, the drug-metabolizing enzyme polymorphisms are foremost in pharmacogenetics.


We hear almost every day about the unwanted effects of prescription drugs and over-the-counter nostrums, of unsafe substances in foods, and of the perils of tobacco smoking and drinking alcohol. We cannot help but wonder why such effects occur in only a fraction of persons exposed, or why a drug that is therapeutic in one person may be ineffective, or even toxic, in another. This is the province of pharmacology. During the period in and around the 1950s, pharmacologists demonstrated, contrary to common belief, that adverse responses accompanying exposure to exogenous substances were closely tied to a person's genetic makeup (Figure 1.1). When this concept was proposed, it was not entirely new because biologists had long understood that the capacity of organisms to respond differently to the environment was genetically determined. Even so, demonstrating that heredity exerted important effects on human drug responsiveness was an innovative step that cast doubt on the notion that the...


Heyser2 1Committee on the Neurobiology of Addictive Disorders, Pearson Center for Alcoholism and Addiction Research, The Scripps Research Institute, TPC-5, La Jolla, CA, USA 2Department of Psychology, Franklin and Marshall College, Lancaster, PA, USA Acamprosate, marketed under the brand name Campral, is an orally administered drug approved in the USA and throughout much of the world for treating alcohol abuse and dependence. Alcohol-use disorders, which include both alcohol abuse and dependence, make up one of the most prevalent categories of substance use disorders in the USA, affecting almost 18 million Americans. The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV APA 1994) characterizes alcohol dependence as a maladap-tive pattern of drinking leading to clinically significant impairment, as manifested by a compulsion to drink, a lack of control over the amount of alcohol consumed and continued drinking, despite a...

General Risk Factors

Involved in prostate carcinogenesis 41,42 . In most studies of alcohol use as a potential risk factor for prostate cancer, no evidence for an association was found (see 12, 43 ). A notable exception is a study by Hayes et al. 44 , who found a positive association in a US case-control study, but only for heavy use of alcohol. This may be related to the fact that prostate cancer risk is elevated in alcoholics with liver disease (see 13, 43 ), probably because of an impaired clearance of estrogens described in men with liver cirrhosis 45,46 .

Patient selection

Phenomenon, and it is especially important in clinical trials to obtain information about past and present psychiatric disorders and treatments, especially mood and anxiety disorders, suicide, and substance and alcohol abuse. Such conditions may be considered exclusion criteria for a trial, and may also serve to moderate the effects of treatment 36 .

Social History

The social history provides valuable insight into the patient's social structure, coping mechanisms, and support systems (Jamison and Virts 1990). A history of substance abuse, employment issues, or family difficulties affects an individual's ability to cope with his her pain. Studies show that patients who are married or have children have a more positive outlook and are better capable of managing their pain. In addition, job satisfaction and one's general attitude toward life play a significant role in a patient's ability to cope with difficulties. The history of drug use or alcohol abuse is another important factor in alerting the physician about potential medication abuse.

Cancer and Nutrition

Many dietary substances are known to produce cancer. Alcohol is an excellent example of one in common usage. In people who both drink and smoke the risk is considerably magnified. The mouth, esophagus, and pharynx are the most frequent sites. These are the areas of most likely contact for both substances. The liver, of course, is also exposed to alcohol, where it is metabolized. One of seven heavy drinkers develops cirrhosis of the liver. It may be no coincidence that most primary liver cancers in the United States originate in cirrhotic livers the remainder may be virally induced. Unfortunately, the list of carcinogens occurring in many foods naturally, as additives, and as a result of storage and even cooking processes, is large and growing. Sodium nitrite, a precursor of carcinogens (nitrosamines), occurs in many foods such as vegetables naturally, and in meat products as an additive. Even where foods contain nitrate rather than nitrite, it is secreted into the saliva following...

Vitamins Vitamin A

Patients using isotretinoin and pregnant women taking valproic acid are likewise at increased risk for vitamin A toxicity (Higdon 2003, Nau et al. 1995). Finally, alcohol consumption decreases the liver toxicity threshold for vitamin A, thereby narrowing its therapeutic window in alcoholics (Leo and Lieber 1999).


Paracetamol has been associated with liver toxicity in association with massive overdose or chronic unintentional overdose in patients with a history of chronic alcohol abuse, malnutrition, and prolonged starvation and it is one of the most common causes of acute liver failure in the USA.109 III Patients consuming more than three units of alcohol per day should consult with their physician before taking any analgesic.95,109 III


Listeria monocytogenes is a Gram-positive rod that produces both acute and chronic meningoencephali-tis. Selective vulnerability of the brainstem to Listeria often results in a pontobulbar encephalitis characterized by fever, ataxia and polyneuritis cranialis. Infection occurs most frequently in infants and the elderly, in alcoholics, in patients with CD4 counts below 50 cells mm3,143 and in HIV patients taking steroids.144 In

Breast Cancer

Breast cancer in premenopausal women. Using a case-control study design, Lee et al. 67 reported a significantly lower risk of breast cancer in premenopausal Chinese women in Singapore who consumed soy. Many studies thus far have attempted to correlate an increase in consumption of dietary estrogens with a decrease in breast cancer risk by measuring urinary excretion of phytoestrogens. Maskarinec et al. 119 conducted a cross-sectional study to investigate the associations between urinary isoflavone excretion and self-reported soy intake of 102 women of Caucasian, Native Hawaiian, Chinese, Japanese and Filipino ancestry. Japanese women excreted more daidzein, genistein, and glycitein than did Caucasian women, whereas Caucasian women excreted slightly more coumestrol than any other group. Equol was excreted at the highest rate by Chinese women, whereas all other women excreted equol at a very low rate. These results demonstrate differential intestinal absorption by ethnic groups. Dietary...

The History

With the beginning of the 20th century and the spring of biological psychiatry, the first twin studies were performed to investigate heritability of mental diseases and psychopathological traits. Ernst Rudin and its group at the Munich Research Institute improved the fist statistical research techniques to quantify the familial concentration of some psychiatric diseases they tended to neglect completely the role of environmental influences, so their results were easily criticized by the so called environmentalists. This widespread interest was particularly flowering in Nazi Germany and research findings about heritability were at the bases of the eugenic movement. The term eugenic was created by F. Galton in 1889. The followers of this doctrine had, as their main wish, to reduce illnesses and abnormality in humankind, through aimed elimination and mating selection (Weber 1997). They sustained that mental illness, feeble-mindedness, criminality, alcoholism and sexual promiscuity were...

Therapeutic Uses

The most common daily dose is 1000 mg, the dose at which epidemiological studies suggest that GI adverse effects are less common than with therapeutic doses of tNSAIDs. Higher doses, which may accomplish complete inhibition of COXs, may approach the adverse effect profile of tNSAIDs. Single doses for children range from 40-480 mg, depending upon age and weight no more than five doses should be administered in 24 hours. A dose of 10 mg kg also may be used.

Increased Infections

Increased infections have been reported in 2-4 of children on the KD (8,27,28). Woody et al. (28), who evaluated neutrophil function in 9 children on the KD, demonstrated that while ketotic, patients had significantly less bacterial phagocytosis and killing. These effects reversed upon discontinuation of the diet. Similar impairments in neutrophil responses have been reported in patients with ketosis from other etiologies, including diabetes mellitus, alcoholism, glycogen storage disease, protein-calorie malnutrition, intralipid infusions, and carbohydrate-restricted weight reduction diets in adults (28). The mechanism of the neutrophil dysfunction is not fully understood but is thought to be related to serum metabolites that affect early events in phagocytosis (28). Only one of Woody's 9 patients experienced serious bacterial infections.

Risk Factors

In the U.S. and other developed countries, the major cause for SCC of the esophagus is smoking and alcohol consumption. The risk of developing cancer was influenced most by the amount of alcohol consumed per day, the lifetime duration of cigarette smoking, the type of tobacco smoked (black tobacco had two-fold higher risk than blond or mixed tobacco), and time since quitting either habit. Recent data suggests that only after abstinence from drinking for 10 years does cancer risk decrease to levels of those who did not drink. After abstinence from smoking for five years, the risk of cancer is cut by 50 .2 Tobacco and alcohol consumption have been found to be more prevalent in patients with EAC as compared with patients with uncomplicated Barrett's esophagus. Recent case-controlled studies suggest that the risk of esophageal and esophago-gastric junction adenocarcinoma is doubled among smokers.2 Although the data suggest that tobacco is an etiologic factor for adenocarcinoma, it does...

Closed trials

The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study and the Beta-Carotene andRetinolEfficacy Trial (CARET) both were carried out in populations at high risk for lung cancer. The ATBC Study investigated the efficacy of vitamin E (a-tocopherol, 50 mg) alone, p-carotene alone (20 mg), or a combination of the two compounds in preventing lung cancer among more than 29,000 male cigarette smokers ages 50-69, with an average treatment followup of 6 years. Unexpectedly, this study showed a 16 higher incidence of lung cancer in the p-carotene group. However, 16 fewer cases of colorectal cancer were diagnosed among men who received vitamin E (ATBC Cancer Prevention Study Group, 1994 Albanes et al., 1996). Further, recent analysis of ATBC followup data found a 36 decrease in prostate cancer incidence and a 41 decrease in mortality from prostate cancer among men receiving vitamin E (Heinonen et al., 1998). In the ATBC Study, the adverse effects of p-carotene were observed at the...


Tremor is usually increased in fatigue, weakness, anxiety, hypercapnia, drug and alcohol withdrawal, and some metabolic and endocrine syndrome (uremia, hypoglycemia, hepatic disease, thyro-toxicosis and heavy-metal intoxication). Some medications increase physiological tremor, e.g. amphetamines, valproic acid, theophyllines, lithium,


Longitudinal Multi-Slice Short-Te 1H MRSI Reveals On Going Brain Metabolite Injury In Treated HIV+ Patients And In Chronic Heavy Drinkers. Proc Intl Soc Mag Reson Med 2004 11 290. and alcohol dependence on brain structures and metabolites quantitative MRI and proton MR spectroscopic imaging. Addiction Biology 2001 6 347-61. quantitative magnetic resonance imaging and magnetic resonance spectroscopic imaging in chronic alcohol abuse. Alcohol Clin Exp Res 2001 25(11) 1673-82. 33. Meyerhoff D, Blumenfeld R, Truran D, et al. Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites. Alcohol Clin Exp Res 2004 28(4) 650-61. changes in chronic, active heavy drinkers. Psychiatry Res 2004 132(3) 209-18


Hydromorphone, (Dilaudid) is a synthetic derivative of morphine prepared by the catalytic hydrogenation and dehy-drogenation of morphine under acidic conditions, using a large excess of platinum or palladium.63 Oxidation of the 6-OH of morphine resulted in a compound with decreased potency. Reducing the 7,8 double bond of morphine increased the flexibility of the molecule and resulted in a compound with slightly enhanced binding. Making both of these structural changes to morphine-produced hydromorphone, a compound approximately 5 times as potent as morphine. Hydromorphone was introduced in 1926 and is available as an immediate release tablet, a liquid, and a suppository. A sustained release form is available in some countries but not in the United States. The sustained release form was removed from the U.S. market in 2005 when studies showed that drinking 8 oz of alcohol (40 ) could cause the drug to be released from the capsule immediately and lead to concentrations that were 5.5...

Vitamin C

Several studies found correlations between vitamin C supplement use and risk for cataract. In our Nutrition and Vision Project (Jacques et al., 1997), age-adjusted analyses based on 165 women with high vitamin C intake (mean 294 mg day-1) and 136 women with low vitamin C intake (mean 77 mg day-1) indicated that the women who took vitamin C supplements for 10 years had > 70 lower prevalence of early opacities (RR, 0.23 CI, 0.09-0.60) (Fig. 22.1A) and > 80 lower risk of moderate opacities (RR, 0.17 CI, 0.03-0.87) at any site compared with women who did not use vitamin C supplements (Fig. 22.1B) (Jacques et al., 1997). Recent re-examination of 600 of the members of the same cohort indicates that comparable data can be anticipated. This corroborated work by Hankinson et al. (1992b) who noted that women who had consumed vitamin C supplements for > 10 years had a 45 reduction in rate of cataract surgery (RR, 0.55 CI, 0.32-0.96) (Fig. 22.1G). In comparison with the data noted above,...

Chronic pancreatitis

The symptoms of pancreatitis can be associated with pancreatic cell death and or with ductal fibrosis and calcification and are generally grouped into acute (isolated episodes with serum amylase and lipase elevations) and chronic (identical symptoms that may lack measurable laboratory abnormalities) forms 37-39 . Whereas acute pancreatitis generally resolves without permanent structural abnormalities, most forms of chronic pancreatitis are associated with permanent abnormalities. Acute-on-chronic episodes may occur in a patient with known chronic changes that become coupled to an acute necrotic episode. Alcohol abuse is the primary etiology in 70-80 of cases of chronic pancreatitis in nontropical regions. Only 5-10 of heavy drinkers develop symptomatic chronic pancreatitis, implying that other etiologic factors (e.g. genetic, infectious, nutritional) also contribute to its development. Other potential causes include a pancreas divisum, genetic causes (hereditary type), previous...


Naltrexone (Fig. 24.13) is a pure opioid antagonist at all opioid receptor subtypes with the highest affinity for the -receptor. Naltrexone is orally bioavailable and blocks the effects of opiate agonists for approximately 24 hours after a single dose of 50 mg. It produces no opioid agonist effects and is devoid of any intrinsic actions other than opioid receptor blockade. Theoretically, it should work well to treat opioid dependence but in clinical practice, patients have shown poor compliance and high relapse rates. Naltrexone has also been studied to treat alcohol dependence with mixed results. To address the compliance issues and effectively remove the choice of taking the antagonist, naltrexone was developed into an extended-release injectable microsphere formulation for IM injection once a month (Vivitrol). This formulation provides steady-state plasma concentrations of naltrexone threefold to fourfold higher than the 50-mg oral dose 4 times a day.119 Currently, Vivitrol is only...


Nalmefene (Revex) is a pure opioid antagonist that is the 6-methylene analog of naltrexone. It is available as a solution for IV, IM, or subcutaneous (SC) administration to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It is longer acting than nalox-one but otherwise has a similar pharmacodynamic and metabolic (3-glucuronidation) profile. Nalmefene has higher oral bioavailability (approximately 40 )123 than naloxone or naltrexone and is currently being investigated as an oral treatment for pathological gambling124 and alcohol abuse.125


Unlike aspirin or ibuprofen, acetaminophen is well tolerated with a low incidence of GI side effects. It also has good oral bioavailability, a fast onset and a plasma half-life of approximately 2 hours after dosing. Although it is a relatively safe pain medication, several precautions should be recognized, including not exceeding the recommended maximum dosage of 4 g d. A lower daily dose of less than 2 g d is required in patients who are chronic alcoholics or have renal

Phenotype Definition

The term alcoholism, which covers a set of complex relationships with alcohol, is no more used in the international literature because of its heterogeneity. An expert group from the WHO, since 1976 (Edward et al., 1976), decided that it was important to distinguish the alcoholic behaviour itself, the syndrome of alcohol-dependence, and the multiple consequences of chronic alcohol intoxication, concerning somatic, psychic and social domains. This perspective was a core element in the building of substance abuse and substance dependence criteria, as they are defined in DSM-III, ICD-10, DSM-IV and DSM-IV-TR. Distinguishing two diagnostic categories is thus generally admitted -alcohol abuse (DSM IV TR) relates to an inadequate use of alcohol, leading to functional impairment or a clinically significant suffering. The core criteria are limited to social, interpersonal, physical or judicial consequences of repeated consumptions of alcohol beverages. -alcohol dependence is characterised by...


Study results from the 1986 NHIS found that 26 percent of American adults took a vitamin A supplement. NHANESIII, 1994-1996 data found the highest mean intake amount of preformed vitamin A for any gender and life stage group was between 895 and 1,503 (g d, and, of those who took vitamin A supplements, approximately 1,500 to 3,000 (g d was the maximum ingested. Therefore, the Food and Nutrition Board of the IOM of the National Academies concluded that the risk for exceeding the UL for vitamin A was small based on this data. Deficiency concerns were also felt to be minimal, except for those individuals within a subgroup of the population at risk for vitamin A deficiency. Based on all the evidence to date, the Food and Nutrition Board has concluded that while carotenoids appear beneficial and are vital for metabolism, more studies need to be evaluated and DRIs for carotenoids cannot be established at this time. At least five or more dietary servings of fruits and vegetables on a daily...

Liver Cancer

Hepatocellular carcinoma develops as a rule in the context of chronic inflammation and liver cirrhosis caused by the hepatitis viruses HBV or HCV, by chronic alcohol abuse, or more rarely by hereditary diseases such as hemochromatosis. Chemical carcinogens such as aflatoxin B1 from the mold Aspergillus flavus act synergistically with the causes of inflammation, in particular with chronic HBV infection. Aflatoxins cause a diagnostic G T mutation at codon 249 of TP53.


Hemochromatosis is a comparatively rare disease, but its pathophysiology is well understood. It provides an example for other, more prevalent, but less well understood factors that cause liver cancer by a basically similar pathway through chronic inflammation and cirrhosis. The most important ones are the hepatitis viruses HBV and HCV, and alcohol abuse (Table 16.1). In a typical Central European population, 3 of all HCC cases might be associated with hemochromatosis, and 30 each with HBV, HCV, and alcohol, the remainder with other known or unknown causes. A rising incidence of HCC in industrialized countries over the last decades is mainly caused by an according increased prevalence of HCV infections. Tellingly, the rise in cancer incidence is delayed by 15 years compared to that of the viral hepatitis. So, this is the period required for development of cirrhosis and cancer. stem cells. These are thought to reside in the ducts of Herring at the origin of the bile duct. Their...

Cluster Headache

(secretion of tears), rhinorrhea (discharge of a nasal mucus), conjunctival injection (bloodshot eyes), and ptosis (drooping of the upper eyelid). Diagnosis is based on symptoms. Cluster headaches are characterized by nightly recurrences usually occurring 1-2 h after falling asleep and are not associated with either aura or vomiting. These headaches recur with regularity for up to periods of 6-12 weeks, followed by symptom-free periods of months to years. Cluster headaches usually last for about 15-180 min. Same orbit is usually involved in recurring bouts. Cluster headaches are common in alcoholics, adolescents, and adult males.

EVH1 Domains

Another interesting class of proteins containing EVH1 domains is the Homer proteins (Shiraishi-Yamaguchi and Furuichi 2007). These proteins are implicated in the formation of oligomeric structures of the post-synaptic density matrix and thereby contribute to synaptogenesis and receptor trafficking. In addition, Homer proteins are directly involved in controlling glutamate levels in the limbo-corticostriatal regions of the brain. Studies of Homer knock-out mice revealed involvement of these proteins in a number of behavioral abnormalities and neu-ropsychatric disorders, such as addiction, depression, epilepsy and schizophrenia (Szumlinski et al. 2006). Homer 2 knockout and overexpression studies in mice, for example, reveal a positive role of the protein in behavior leading to increased alcohol consumption (Szumlinski et al. 2005). The role of the EVH1 domain in the development of these diseases is not understood, but specific inhibition of Homer EVH1 domains would enable their...

Stomach Cancer

The decreased incidence of 'classical' gastric cancer in industrialized countries is partly offset by a rising incidence of cancers of the esophagus and the upper parts of the stomach. These cancers are associated with alcohol consumption and smoking, and they may be promoted by enhanced acidity of the stomach juice as a consequence of H. pylori eradication. They are also typically associated with metaplasia.


Absence epilepsy J uptake epilepsy, epileptic syndromes, and alcoholism GABA-T modifications DP + anxiety and panic disorders SZ J PBR DP PBR Platelets express GABA transporters and the uptake of this amino acid has been reported disrupted in patients affected by absence epilepsy, although the functional impact of the antiepileptic drugs taken by the patients has not been completely clarified. Also GABA transaminase (GABA-T) has been studied, mainly in a setting of various epileptic syndromes, such as juvenile myoclonic, refractory localization-related, and childhood absence epilepsy, showing different modifications. GABA-T represents the main enzyme responsible for GABA catabolism and the inhibition of this enzyme produces a considerable elevation of GABA concentrations often the modulation of such elevation has been correlated with many pharmacological effects, mainly in the field of antiepileptic drugs. GABA-T activity in blood platelets might be altered also in some...

Future Directions

There are a number of known demographic and environmental factors, independent of schizophrenia, that are associated with oxidative stress (Bridges et al., 1993) and need to be taken into account. These include diet, cigarette smoking (Halliwell, 1993), alcohol consumption (Nordmann et al., 1992), environmental pollutants (Papas, 1996) and co-morbid medical conditions. These factors could be additive to the already existing oxidative stress and membrane deficits in schizophrenia.

Acute Pain

In surgical pain, other therapeutic options include alternative route of administration of either opioid, local anesthetic, or both. The use of regional analgesia (e.g., intrathecal or epidural techniques) and or peripheral nerve blockade is used to increase control of pain in addicted patients. In certain cases, pain treatment may require extensive and sympathetic blockade to relieve acute pain such as during major surgery or in profoundly severe acute pains refractory to other modalities of treatment. Patient-controlled analgesia (PCA) modality is often withheld from these individuals because of the concern that self-administered analgesic delivery may reinforce drug-seeking behavior (Sinatra 1998), and neural blockade or epidural analgesic techniques are substituted. More recent thinking allows selected patients presenting with cocaine and alcohol abuse to use PCA in well-supervised settings. Patients with a history of chronic pain and significant opioid tolerance require increased...

Chronic Pain

A history of substance abuse has been previously considered a contraindication to opioid therapy for chronic pain. It appears that individuals with a prior history of recent substance abuse are more likely to have abuse recurrence than individuals with a distant polysub-stance abuse or isolated alcohol abuse. Currently, opioid therapy in patients with a recent history of substance abuse is controversial. Existing studies report mixed results. Preventing or detecting addiction recurrence is key.

Ischaemic stroke

Following the acute phase of ischaemic stroke, blood pressure should be measured and treatment initiated to achieve a target blood pressure of < 130 80 mmHg (see section 2.5). Beta-blockers should not be used in the management of hypertension following a stroke, unless they are indicated for a co-existing condition. All patients should be advised to make lifestyle modifications that include beneficial changes to diet, exercise, weight, alcohol intake, and smoking.

Antimalarial Agents

Porphyria cutanea tarda, characterized by fluid-filled vesicles and bullae on sun-exposed areas, can be either genetic or associated with alcohol abuse or hepatitis C. Although the associated iron overload is treated with phlebotomy, the dermatologic manifestations sometimes are treated with antimalarial agents. These patients require reduced doses because of the potential for hepatotoxic-ity, as manifested by elevated transaminase levels, and the rapid excretion of large amounts of uro-porphyrins in the urine that can occur with usual doses. Low-dose twice-weekly administration is effective and avoids these side effects.


Cautions Hypothyroidism should be managed adequately before starting treatment with a statin (see p. 161). Statins should be used with caution in those with a history of liver disease or with a high alcohol intake see also Hepatic impairment, below. There is little information available on a rational approach to liver-function monitoring however, a NICE guideline1 suggests that liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other Side-effects The statins can cause various muscular side-effects, including myositis, which can lead to rhab-domyolysis. Muscular effects are rare but often significant (see Muscle Effects below). Statins can cause gastro-intestinal disturbances, and very rarely pancreatitis. They can also cause altered liver function tests, and rarely hepatitis and jaundice hepatic failure has been reported very rarely. Other side-effects include sleep disturbance, headache,...


Toxic effects associated with rifampin are relatively infrequent. It may, however, interfere with liver function in some patients and should neither be combined with other potentially hepatotoxic drugs nor used in patients with impaired hepatic function (e.g., chronic alcoholics). The incidence of hepatotoxicity was significantly higher when rifampin was combined with isoniazid than when either agent was combined with ethambutol. Allergic and sensitivity reactions to rifampin have been reported, but they are infrequent and usually not serious. Rifampin is a powerful inducer of hepatic cytochrome P450 oxygenases. It can markedly potentiate the actions of drugs that are inactivated by these enzymes. Examples include oral anticoagulants, barbiturates, benzodiazepines, oral hypoglycemic agents, phenytoin, and theophylline.

M5 Receptors

The human M5 receptor gene (CHRM5) is located on chromosome 15q26 and consists of a single coding exon and three alternatively spliced 5'-UTRs (Anney et al. 2007). The NCBI database contains > 200 SNPs of this gene. We have identified only a single study linking a polymorphism of the M5 gene to phenotype (Anney et al. 2007). In that study, a non-coding C > T SNP (rs7162140) was reported to have a prevalence of 19 and to be associated with the number of cigarettes smoked and cannabis dependence but not with nicotine or alcohol dependence in a sample of 815 Australians of European descent.


Chemotherapy, alcoholism, diabetes, and human immunodeficiency virus acquired immunodeficiency syndrome), mechanical hyperalgesia was reduced by spinal intrathecal administration of antisense oligonucleotides to TRPV4 (Alessandri- Haber et al., 2004, 2006). Mechanical hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in the TRPV4 knockout mice (Alessandri - Haber et al., 2008- . Taxol - -nduced painful peripheral neuropathy could be treated by gene silencing of TRPV4 (Alessandri-Haber et al., 2004), and the induction of osmotic and mechanical hyperalgesia was absent in trpv4- mice (Alessandri-Haber et al., 2006).

Matthias C Lu

Epilepsy is the most prevalent neurological disorder affecting more than 0.5 of the world's population.1 It is characterized by recurrent seizures, unprovoked by any identifiable causes. The etiology of epilepsy is largely unknown even though recent evidence suggests that it may have a genetic component associated with its disease devel-opment.2,3 Seizures, on the other hand, are symptoms of disturbed electrical activity in the brain characterized by episodes of abnormal, excessive, and synchronous discharge of a group of neurons within the brain that cause involuntary movement, sensation, or thought.4 It is generally agreed that seizures may result from primary or acquired neurological disturbances of brain function as a result of an imbalance between excitatory and inhibitory processes in the brain. There are many possible causes of seizures including brain tumors or infections, head trauma, neurological diseases, systemic or metabolic disorders, alcohol abuse, drug overdose, or...

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