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This is the first study that we are aware of that followed the histopathological progression of the liver disease that was caused by the combination of both chronic alcohol use and cyanamide, an antidipsotropic agent. Two sequential liver biopsy specimens were obtained on 29 alcoholics who relapsed with varying histories of cyanamide treatment. Cyanamide induced ground-glass inclusions (GGIs) in the hepatocytes. Two groups were identified, depending on whether GGIs proliferated or regressed, which was, in turn, found contingent on the duration of cyanamide treatment and the drug-free period. Group 1 included 14 cases in which GGIs either emerged only in the second biopsy specimen or else were increased in the second specimen as compared in the initial specimen. Group 2 composed of 15 cases in which GGIs were either not observed in either specimen or decreased in the second specimen as compared in the initial specimen. Acidophilic bodies were sequentially increased in five cases (36%) of group 1 and in none of group 2. The severity of portal inflammation worsened in 10 cases (71%) of group 1 but in 2 cases (13%) of group 2, although the changes in fibrotic process did not differ between two groups. These differences could not be explained on the basis of the daily ethanol consumption and the length of relapses of the two groups. Thus, when cyanamide-treated alcoholics relapsed, the combined effect of cyanamide and alcohol produced the development of acidophilic bodies and portal inflammation along with the emergence of GGIs.

Despite a recent decline in per capita alcohol consumption, alcoholism remains a serious public health problem in France. Pharmacotherapy is used to make withdrawal from alcohol easier and to help maintain abstinence. The recent development of effective pharmacologic treatments for alcoholism has increased interest in this approach to therapy. To determine the most appropriate form of pharmacotherapy for treating alcohol dependence, a meta-analysis of randomized controlled studies published between 1960 and 1993 was performed. We found that several pharmacotherapeutic agents had demonstrated safety and efficacy on different periods of follow-up, including acamprosate (long term), naltrexone (intermediate term), fluoxetine and citalopram (short term). Studies of zimeldine, nialamide, L-dopa, viloxazine, and tetrabamate failed to demonstrate efficacy for these agents in the treatment of alcoholism. Results were ambiguous or mixed for lithium, phenytoin, bromocriptine, apomorphine, and buspirone. Continued research is needed to identify the most appropriate patients to receive treatment with specific forms of pharmacotherapy.

The reported ability of benzodiazepines to increase human erythrocyte aldehyde dehydrogenase (ALDH) activity and reverse the disulfiram-induced inhibition of ALDH was reexamined. When ALDH activity assays were carried out spectrophotometrically on a hemoglobin-free lysate of human erythrocytes with propionaldehyde as substrate, addition of diazepam (10 mumol/l) did not affect the enzyme activity. When assays were carried out on intact or hemolysed erythrocytes using high performance liquid chromatographic technique with 3,4-dihydroxyphenylacetaldehyde as substrate, no significant increase in erythrocyte ALDH activity was found in the presence of chlordiazepoxide, oxazepam, diazepam, or desmethyldiazepam in the concentration range 1-20 mumol/l. Rather, a significant decrease (about 50%) in activity was obtained when lysed cells were incubated with 20 mumol/l chlordiazepoxide. Diazepam inhibited the rat liver mitochondrial low Km ALDH activity by about 50%. Disulfiram inhibited the ALDH activity almost completely in assays on human erythrocyte or rat liver mitochondrial ALDH. The ALDH activity was not regained by the subsequent addition of diazepam, nor was the effect of disulfiram reduced when diazepam was added prior to disulfiram. In an alcoholic subject who was followed during onset of disulfiram (Antabuse) therapy, the concurrent use of diazepam did not prevent a rapid decline in blood ALDH activity. The present results suggest that benzodiazepines do not increase ALDH activity in vitro, nor interfere with the inhibition of ALDH by disulfiram.

Although past alcoholism treatment in Germany has primarily focused on psychotherapy, new advances in pharmacotherapy are expanding therapeutic options. Recent biomedical studies have produced new theories about how alcohol affects neurotransmitters in the brain. These studies have led to new pharmacologic strategies for the treatment of alcoholism using dopamine agonists and antagonists, serotoninergic agents, glutamate antagonists, and opiate antagonists. While preliminary studies of these agents offer encouraging results, it remains to be demonstrated which agent(s) will provide effective pharmacotherapy for this disease.

Acamprosate is a relatively new drug that appears to be clinically useful in the treatment of alcohol dependence. Although it has proved effective in reducing relapse into drinking in clinical trials its exact mechanism of action is uncertain. Evidence is presented that the drug does not act in any of the conventional ways to reduce alcohol intake and it is proposed that it may be a novel kind of agent that suppresses "craving". On the basis of its known pharmacological effects in pre-clinical studies it is suggested that acamprosate may reduce craving that is associated with conditioned withdrawal. In addition to the potential therapeutic value of acamprosate, the drug may be useful because work directed toward understanding its mechanism of action may shed light on some of the fundamental processes that govern alcohol abuse and relapse in weaned alcohol dependent patients.

The effects of a novel antialcoholic medication medichronal on the serotonine concentration in blood of patients with second stage alcoholism was investigated. It has been discovered that remission in 75% of the patients was connected with its hyper- and hyposerotoninemic influence, depending on the initial lowered or increased serotonine content. Similarity of medichronal and unithiol effects was observed in the form of palyndromoinversion regulation of serotoninergic activity. In a portion of the patients the increased, compared to healthy persons, serotonine concentration before and after the treatment does not differ from the average values in the whole group.

There is increasing evidence that "anticraving" drugs are promising agents in the treatment of alcoholics. Clinical studies indicate favorable effects of drugs with different pharmacological profiles (e.g., dopaminergic, serotonergic, anti-opioidergic, antiglutamatergic) on abnormal drinking behavior and relapse tendencies. Interactions with the limbic reward system seem to be involved. As several drugs will probably be registered in Germany, the need for integrating these drugs in a complex rehabilitation program is emphasized. Many clinical issues regarding the practical use of these drugs await further clarification.

Chronic alcoholic intoxication is followed by a fall in 3H-(D-ala-2,D-leu-5)-enkephalin affinity of mu-opioid receptors with their unchanged concentrations in the rat brain cortex, by reductions in the tissue and plasma levels of beta-endorphine and met-enkephalin. A daily administration of reaferon in a dose of 10,000 IU during two fortnights completely restored both the binding affinity of the receptors and the concentrations of the peptides tested: those of beta-endorphine in the adenohypophysis and plasma and those of metenkephalin in the adrenals and plasma.

Although studies repeatedly demonstrate that alcoholics who consistently take disulfiram experience more favorable drinking outcomes, serious problems with compliance among the majority of alcoholic patients have reduced the effectiveness of disulfiram as a therapeutic adjunct. In general, alcoholism counseling with disulfiram simply prescribed seems no more effective than counseling without disulfiram (Fuller et al. 1986). Problems with compliance as well as problems with acceptance by patients and likely by clinical staff reduce the utility of disulfiram in the treatment of alcoholism. Implants, incentives, and various forms of observed or supervised disulfiram have been studied as possible solutions to the problems with compliance. Disulfiram implants appear largely ineffective due to failure to release adequate levels of disulfiram and risks of surgical complications and rejection. Newer techniques (see Allen and Litten 1992) may ultimately lead to a more effective implant. Incentives with personally relevant and obvious reinforcement value such as money, avoidance of incarceration, remaining employed, and continuation of methadone for opiate addicts, have been used effectively. Enhancement strategies with less tangible incentives also show promise. Among these are feedback on results of biochemical measures of disulfiram compliance and continuation in a familiar treatment program. Although each of the studies of incentives suffers from specific methodological limitations, the findings uniformly demonstrate better disulfiram compliance, less drinking, and better clinical outcomes for those who received a meaningful incentive for taking disulfiram. External monitoring of the patient taking disulfiram to assure compliance is typically used in studies evaluating incentives for taking the medication. Observed or supervised disulfiram in its own right and without tangible incentives also has received increasing attention as a method for enhancing compliance. Incorporation of such a strategy would seem to have potential for wide applicability in alcoholism treatment programs. Three forms of supervised disulfiram have been studied: (1) a written disulfiram contract, such as in BMT, with instructions about the benefits of the disulfiram contract and methods to establish disulfiram use as a daily habit and specifying that the alcoholic will take disulfiram daily while the spouse observes, that the couple will mutually thank each other, and that they will refrain from arguments or discussions about the alcoholic's drinking; (2) the disulfiram contract used in CRA, which is identical in form to the BMT contract except that talk about drinking is not prohibited; and (3) supervised disulfiram without a written contract, special instructions, or explicit verbal thanking. Studies of these three forms of observed disulfiram have been among the better controlled studies. Each approach has produced very promising results. A disulfiram contract with BMT produced less short-term drinking than disulfiram accompanied either by couples or individual counseling. Unfortunately, the superior BMT drinking results eroded because many couples discontinued their disulfiram contract after treatment ended (O'Farrell et al. 1985, 1992). Adding couples RP sessions after BMT led to better fulfillment of the disulfiram contract and better drinking and marital outcomes than BMT alone. These better RP outcomes persisted for 18 to 24 months after BMT for the entire sample and throughout the entire 30-month followup after BMT for those with more severe drinking and marital problems (O'Farrell et al. 1993). Thus, disulfiram contracts used with BMT are associated with less drinking and greater disulfiram compliance, while the specific contribution of disulfiram contracts to BMT remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)

There are substantial differences between the objectives and processes of normal grant-funded research and those of commercial pharmaceutical development. These differences are explained with respect to clinical trials design in alcohol addiction, strategies for maximizing the success of controlled trials in drug development in this area, and avoidance of problems in the conducting of clinical trials subject to audit. Also discussed are possible new pharmacological interventions in alcohol use disorders and the need to recognize the usefulness of medications across the whole range of clinical presentations.

Treating patients with stage-II alcoholism with medichronal and unithiol sharply decreases blood levels of alcohol and acetaldehyde. Medichronal restores the decreased level of norepinephrine excretion in 25% of patients and the increased level of epinephrine in 43%. The high baseline concentration of serotonin dropped in 41%, however, its level remained higher than in the controls. There was a negative correlation between the changes of ethanol concentrations and the excretion of norepinephrine. There was a direct dependence between the changes in the norepinephrine/epinephrine ratio and the serotonin concentration.

The application of the novel antialcoholic drug Medichronal mainly results in normalization of dyscatecholaminemias, by lowering or elevating noradrenaline or adrenaline levels. This effect is similar to that produced by unitiol that is conventionally used in nacrological care. The changes in catecholamine levels occur in various dyscatecholaminemias characterized by a high or low excretion of biogenic monoamines. Before and after therapy, in some patients, the concentrations of catecholamines do not differ from those in healthy persons.

This paper describes the findings of a qualitative research study aimed at eliciting the perspectives of problem drinkers concerning the drug disulfiram (Antabuse). A grounded theory model of Commitment to Abstinence, which was generated from the study data, is presented. The influence of disulfiram upon this model is examined via the perspectives of disulfiram users. It is suggested that the drug could be used in a flexible way with some clients to their advantage. The significance of the study and the derived model for mental health nursing is discussed, the value of the model as an assessment tool is explored and other more generic applications are suggested.

The current knowledge on the interactions between alcohol and the central nervous system moves very quickly. Moreover the scientific advances follow the three axes of our understanding, biological, psychological and sociological, but this implies some dispersion. The present paper focuses on recent advances in neurobiology of alcoholism and shows new perspectives in pharmacological interventions, with new drugs. In the same time, the psychodynamic and systemic understandings are evoked, in a purpose of integration and of public health policy.

Patients with alcohol problems come to their primary care physicians at different points along the spectrum of experiences with alcohol; therefore, physicians need to be able to respond with a variety of interventions. In addition, patients present in different stages of change, and physicians need to be aware of where the patient is in that continuum. Evidence shows that less intensive, outpatient treatment may be as beneficial as inpatient treatment for some patients and that primary care physicians can offer some of their patients relatively simple interventions that are effective. Medications such as disulfiram offer little in the treatment of alcoholism but may be of benefit in selected situations. Of greater benefit are more complex psychosocial interventions carried out by a team of health care professionals.

Many pharmacological agents have been proposed for the treatment of drinking problems. However, there are many pitfalls in the assessment of the clinical interest of those drugs. In this paper, we propose a new classification of drugs of interest for treating alcohol abuse and related problems. We also review the major clinical studies about those pharmacological agents and discuss some peculiar aspects of those trials think to be important to develop better strategies for the evaluation of pharmacotherapy of alcoholism.

In an article published in 1984 Teeling-Smith referred to pharmacological treatments for alcohol problems as a challenge to pharmaceutical innovation. This challenge still exists and seems most likely to be met by the application of drugs developed for some other purpose to the treatment of alcohol abuse, rather than the empirical development of drugs for treating alcohol abuse per se. The papers which follow in this symposium enlarge upon some of the areas covered in this brief survey.

Many pharmacological agents have been proposed for the treatment of drinking problems. However, there are many pitfalls in the assessment of the clinical interest of those drugs. In this paper, we propose a new classification of drugs of interest for treating alcohol abuse and related problems. We also review the major clinical studies about those pharmacological agents and discuss, through the studies about serotonergic agents, lithium salts, disulfiram and related compounds, some peculiar aspects of those trials that we think to be important to develop better strategies for the evaluation of pharmacotherapy of alcoholism.

The past decade has witnessed major advances in understanding of neural functioning and neurobiological bases of alcohol consumption. Concurrent with this, a range of exciting investigations have been conducted on pharmacologic agents that may curb drinking behavior. Research is reviewed on several promising medications influencing neurotransmitter and endocrine systems with particular attention to the serotonergic and opioid systems. Following this overview, recommendations are offered regarding research methodology to support future pharmacotherapy trials.

Neurobiological research over the past decade has greatly expanded our knowledge of alcohol's interaction with the nervous system and promises significant improvement in pharmacological treatment for all phases of alcoholism. Although no new treatment has yet become standard clinical practice, over the next decade benzodiazepine receptor antagonists and inverse agonists should improve treatment of acute alcohol intoxication, adrenergic agents and anticonvulsants should improve treatment of acute alcohol withdrawal, and serotonin uptake blockers and mu opiate receptor antagonists should improve long-term treatment of alcohol dependence. Future clinical research should reduce the current lack of knowledge on pharmacological treatment of alcoholism in special populations such as women, the elderly, and those with concurrent psychiatric diagnoses.

This paper presents an overview on pharmacologic treatment of alcoholism. A wide range of drugs have been tested over the years, some showing a reduction of alcohol drinking in alcoholics. However, at present, there is little evidence that pharmacotherapy is effective in the rehabilitation of alcoholics. Although research in this area still has several methodological problems and much needs to be done, a greater understanding of the neuropharmacology and neurobiology of alcohol use and abuse will certainly open new avenues for investigation and drug development. Patient-treatment matching and the combination of two or more modalities of intervention may also help increase overall effectiveness of alcohol treatment.

The past 10 years have witnessed important advances in research on pharmacotherapy for alcoholism. Promising drugs are discussed under six headings: agents to treat alcohol withdrawal; anticraving agents; agents that make drinking an aversive experience; agents to alleviate concomitant psychiatric problems; agents to treat concurrent drug abuse; and amethystic ("sobering-up") agents. Research on the drug classes is summarized and clinical issues surrounding specific agents and alcoholism pharmacotherapy in general are discussed. Finally, long-range therapeutic implications of recent findings on the actions of alcohol on basic mechanisms of the brain are offered.

This paper is a brief review which deals with research findings, clinical issues, and strategies in the pharmacotherapy of alcoholism. The pharmacotherapy is presented according to different clinical phases of the alcoholic process. The acute intoxicated patient receives supportive treatment, to be clinically observed to prevent severe respiratory depression, aspiration of vomitus, and severe alcohol withdrawal syndrome. Benzodiazepine therapy is the mainstay in treating alcohol withdrawal syndrome. Disulfiram is the only chemical used in the United States to deter the alcoholic patient from further alcohol drinking. Although there is not a specific agent for alcoholism per se during the sobriety state, the alcoholic patients' concurrent underlying psychiatric conditions (such as schizophrenia, anxiety, and depression) should be treated properly and adequately.

Chemical aversion treatment is one of the most promising modalities currently available for treatment of alcohol dependence. This review highlights potentially fruitful areas for future investigational efforts and poses a number of specific empirical questions. Investigation of issues delineated in this report would advance understanding of pharmacological aversion therapy vis-à-vis utility and mechanisms of action.

Serum lipid peroxidases (LPx) concentration was assayed in the following groups: 25 patients with diagnosis of acute alcohol intoxication, 20 patients during alcohol abstinence and 30 healthy control individuals. In 25 patients the assessments were carried out twice: before and on the 3-7 day of detoxification. The serum LPx had been significantly higher in all patients during the acute intoxication period (4.33 +/- 0.20 nmol/l; p less than 0.01). In 38% of them the LPx concentration was falling down after detoxication. There were no difference in LPx concentration between the group of abstinents and the healthy controls. The results point to dependence between clinical state of alcoholics and serum LPx level.

Current criticisms of chemical aversion therapy are delineated and their validity assessed. Data pertaining to the effectiveness, acceptability, intrusiveness, availability of alternative treatments, cost-effectiveness, and theoretical foundations of chemical aversion therapy are examined. It is concluded that available evidence supports the efficacy of chemical aversion therapy with respect to production of conditioned aversion to alcohol and treatment outcome.

We have investigated the effectiveness of seven new beta-lactam antibiotics, azlocillin, piperacillin, ceftazidime, cefsulodin, cefoperazone, latamoxef (moxalactam), and cefotaxime, against acute pulmonary exacerbations caused by Pseudomonas aeruginosa in cystic fibrosis. Three hundred and fifty-five strains of Ps aeruginosa isolated from 310 sputum cultures (190 cystic fibrosis patients) were tested for susceptibility to the drugs by determination of minimal inhibitory concentrations (MIC). The highest activity was shown by ceftazidime (6% resistant strains) followed by cefsulodin and piperacillin (15 and 16% resistant strains); very low activity was found for cefotaxime and latamoxef (moxalactam). Ceftazidime was the most active drug against 32 pseudomonas isolates that were resistant to both carbenicillin and aminoglycosides (78% susceptible). A randomized, double-blind trial of azlocillin, piperacillin, ceftazidime, cefsulodin or cefoperazone was performed in 111 cystic fibrosis patients with predominant and susceptible pseudomonas in their sputum. Results were evaluated by a clinical, radiological and bacteriological scoring system: the best results were obtained with ceftazidime, followed by cefsulodin and piperacillin. However, pseudomonas was eradicated in only 22 (23%) of the cases with the most active drugs and persisted or reappeared in all the cases 1 to 3 months later. Ceftazidime always eradicated Staph. aureus and Haemophilus influenzae associated with pseudomonas. Similar eradication occurred nearly always with cefsulodin but rarely with the other drugs. No serious drug reaction occurred but a later fever and rash with piperacillin, transient diarrhoea with cefoperazone, vomiting with cefsulodin, and very frequent eosinophilia with ceftazidime should be mentioned. These five drugs offer, in varying degree, alternatives to traditional anti pseudomonas antibiotics in cystic fibrosis pulmonary infections, but they should be used only against well-proven resistant strains. Ceftazidime is best and cefotaxime and latamoxef (moxalactam) least useful.

Twenty-eight patients with severe cutaneous infections received cefoperazone, 2 grams intramuscularly twice a day for seven days. A wide range of gram-positive and gram-negative pathogens were isolated from admission cultures. All patients showed rapid clinical improvement. Two patients did not complete the full course of therapy because of intervening medical problems unrelated to the antibiotic. No significant side effects were noted. Relapses or reinfections occurred in two patients. In conclusions, cefoperazone is a safe and effective antibiotic for use in skin infections requiring parenteral therapy.

The author reviews the major advances in concepts and methods that have been made in the treatment of alcoholism over the past decade but finds little change in the everyday operation of treatment programs. He examines the ideological differences between professionals and paraprofessionals in the field, the changes in treatment goals that have been made, the different types of alcoholic patients and their different needs and responses to treatment, the uses and misuses of drug therapies, the relatively unexamined values of psychotherapy, the recently successful behavioral therapies, and treatment delivery systems and their evaluation.

This review critically examines the literature of the past 10 years relating to the use of drugs in treating alcohol intoxication, withdrawal and dependence. Emphasis is given to those studies that have current and potential future clinical relevance. Although research regarding the pharmacological treatment of alcohol disorders still suffers from methodological flaws and lukewarm acceptance, the recognition of this area as a legitimate and fruitful field of study is increasingly apparent.

A procedure is developed for determination of the efficiency of the antialcoholic drugs' action on the system of ethanol oxidation in vitro: alcohol dehydrogenase by the direct and reverse reactions and aldehyde dehydrogenase of subcellular fractions of the rat liver. This procedure is also used to determine the antialcoholic activity of a number of new compounds and to compare them with disulphiram (antabus, teturam), the known antialcoholic drug.