Ground-glass hepatocellular inclusions are associated with polypharmacy.

Ground-glass (GG) hepatocytes are classically associated with chronic hepatitis B (HBV) infection, storage disorders, or cyanamide therapy. In a subset of cases, an exact etiology cannot be identified. In this study, we sought to characterize the clinical, histological, and ultrastructural findings associated with HBV-negative GG hepatocytes. Our institutional laboratory information system was searched from 2000 to 2019 for all cases of ground-glass hepatocytes. Ten liver biopsies with GG hepatocellular inclusions and negative HBV serology, no known history of storage disorders, or cyanamide therapy were reviewed. Half of the patients had history of organ transplantation and/or malignancy. These patients took on average 8.1 medications (range: 3-14) with the most common medications being immunosuppressive and health supplements. Histologically, GG hepatocytes show either peri-portal or centrizonal distribution. The inclusions are PAS-positive and diastase sensitive. Electron microscopy showed intracytoplasmic granular inclusions with low electron density, consistent with unstructured glycogen. In summary, GG hepatocytes are a rare finding in liver biopsies, but are more common in patients with hepatitis B. They can also be seen in HBV-negative patients who have polypharmacy. In these cases, they are the result of unstructured glycogen accumulation putatively due to altered cell metabolism.

Aldehyde Dehydrogenase Inhibition Ameliorates Cardiac Dysfunction and Exacerbates Hypotension Caused by Alcohol in Female Rats.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) protects against alcohol-evoked cardiac dysfunction in male rodents, but its role in the estrogen (E2 )-dependent hypersensitivity of female rats to alcohol-evoked myocardial oxidative stress and dysfunction is not known. METHODS: We addressed this question by studying the effect of cyanamide (ALDH2 inhibitor) on cardiac function, blood pressure, alcohol-metabolizing enzyme (alcohol dehydrogenase, cytochrome P450 2E1, catalase, and ALDH2) activities, and cardiac redox status (reactive oxygen species, ROS; malondialdehyde, MDA) in the absence or presence of ethanol (EtOH) in female sham-operated (SO) and ovariectomized (OVX) rats. RESULTS: Cyanamide attenuated the EtOH-evoked myocardial dysfunction (reduced dP/dtmax and LVDP) in SO rats. EtOH, cyanamide, or their combination did not alter dP/dtmax or LVDP in OVX rats. Cyanamide induced cardiac oxidative stress and abrogated the subsequent alcohol-evoked increases in ROS and MDA levels in SO rats. Neither EtOH nor cyanamide influenced ROS or MDA levels in OVX rats. Importantly, cyanamide exaggerated EtOH-evoked hypotension in SO and uncovered this hypotensive response in OVX rats, which implicates ALDH2 in the vasodilating effect of EtOH. CONCLUSIONS: Contrary to our hypothesis, cyanamide attenuated the E2 -dependent cardiac dysfunction caused by alcohol, likely by preconditioning the heart to oxidative stress, while exacerbating the vasodilating effect of alcohol. The latter might predispose to syncope when cyanamide and alcohol are combined in females.

Tolerance to disulfiram induced by chronic alcohol intake in the rat.

BACKGROUND: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. METHODS: Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. RESULTS: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. CONCLUSIONS: Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.

Problem drinking in relation to treatment outcome among opiate addicts in methadone maintenance treatment.

This study analyzed indicators of alcohol-related problems in opiate addicts before, during, and after leaving methadone maintenance treatment (MMT), in relation to illicit drug use and retention in treatment. The study was based on 204 patients, admitted to MMT for the first time between 1 January 1995 and 31 July 2000, and followed until 31 December 2000. Three measures were used to indicate alcohol use and alcohol-related problems; records of hospital care with an alcohol-related diagnosis, any treatment with alcohol-sensitizing drugs (disulfiram or calcium carbimide) during MMT, and results of the 5-hydroxytryptophol to 5-hydroxyindoleacetic acid ratio (5HTOL/5HIAA) in urine, a sensitive biomarker for recent drinking. Use of illicit drugs was determined by routine urine drug testing. About one third of the patients (n = 69) had a lifetime prevalence of hospital treatment for an alcohol-related diagnosis, 45 of whom had been hospitalized (mean 4.2 stays) prior to the start of MMT. There was a significant association (p<0.05) between the number of alcohol-related diagnoses prior to treatment and a positive 5HTOL/5HIAA test during MMT. The alcohol indicators first became positive on average 1.6 years after admission to treatment, compared with after about 4 months for illicit drugs. Use of cannabis or benzodiazepines was significantly associated with alcohol use. Female methadone patients with indications of alcohol-related problems relapsed more often into illicit drug use than did women without such indications (3.9 vs. 2.5 relapse periods/year; p<0.005), whereas no significant association was found for men. The results of the present study indicate that drinking problems among patients undergoing MMT is associated with an increased risk of relapse into illicit drug use and with discharge from treatment. Concurrent treatment of alcohol-related problems, including systematic monitoring of alcohol use, therefore should be recommended to reduce the risk for relapse into illicit drug use and improve overall treatment outcome in MMT.

Calcium carbimide--ethanol interaction.

Each of 4 male alcoholic subjects received 0.7 mg/kg calcium carbimide (CC) orally 12 hr before ingestion of 0.25 gm/kg ethanol on 3 separate occasions. The CC-ethanol interaction consisted of increased blood acetaldehyde level and elevated heart rate. For each individual there was small variability in the area under the curve (AUC) values of the blood ethanol level--time course profiles for the 3 experiments, indicating a consistent extent of ethanol absorption. For subjects 1, 2, and 3 there was appreciable intraindividual variability in the AUC and the peak blood acetaldehyde levels of the blood acetaldehyde level--time course curves; the variation in these parameters was small for subjects 4. The intraindividual variability in the peak heart rate response was small for subjects 1 and 2 and appreciable for subjects 3 and 4. Regression analysis of the blood acetaldehyde level--heart rate data for each of the 3 experiments conducted on the 4 subjects revealed that there were positive, linear correlations. There was appreciable intraindividual variability in the slope values for the 3 experiments. The results of this study, conducted on 4 male alcoholics, suggest that for other alcoholic subjects there could be appreciable intraindividual variability in the intensity of the CC-ethanol interaction.

The role of drugs in the treatment of alcoholism.

Many drugs are used in alcoholism treatment with the aim of reducing alcohol consumption and correcting alcohol-related psychosocial problems that lead to excessive drinking or result from it. Alcohol-sensitising drugs are used to reduce alcohol consumption with the expectation that improvement in other problem areas will follow. Drugs that share sedative-hypnotic actions with and cross-dependence to alcohol are often used during acute alcohol withdrawal reactions for symptomatic relief, to prevent major withdrawal symptoms, and to prevent and treat seizures. Alcohol abuse may be a form of self-medication, and treatment of an underlying psychiatric disorder, such as depression (with antidepressants), anxiety (with anxiolytics) or psychosis (with antipsychotics), is expected to reduce alcohol consumption. Pretreatment medical and psychiatric assessment of the patient is necessary to ensure that the drug therapy is appropriate to the patient's therapeutic goals and medical/psychological status. Use of the drug must be systematic and carefully monitored; the duration of treatment is determined individually for each patient on the basis of the response to the treatment as well by the development of adverse clinical effects. Ideally, the drug therapy allows the patient to establish resources necessary for continued abstinence after the drug treatment is stopped.

Pharmacologic treatment of chronic alcoholism.

Of the many drug therapies mentioned in this review, only the alcohol-sensitizing drugs have current therapeutic applications in primary alcoholics. When alcohol abuse occurs in association with anxiety, depression, or schizophrenia, treatment with the anxiolytic, antidepressant, and neuroleptic drugs, respectively, may facilitate the alcoholic's ability to participate in other programs. Patients should receive drugs that are appropriate to treatment goals as well as to their psychosocial status. Even if a drug therapy is shown to be efficacious under controlled experimental conditions, its effectiveness may be compromised by a large number of factors that include poor compliance by the patient, a lack of a treatment strategy, or failure to optimize the treatment conditions. New pharmacotherapies with actions directed at central neurochemical pathways mediating alcohol consumption are urgently needed. However, even if such agents become available, they too will only be adjuncts to behavioral and social therapies directed at stabilizing all aspects of the alcoholic's life.

Pharmacological treatment of alcohol intoxication, withdrawal and dependence: a critical review.

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.

Rehabilitation for alcoholics.

Chemotherapy, psychotherapy, behavior modification, and participation in Alcoholics Anonymous have been used successfully to treat the alcoholic patient, but all have limitations and some have potential dangers. All require long-term follow-up and family participation.

Calcium carbimide in alcoholism treatment. Part 2: Medical findings of a short-term, placebo-controlled, double-blind clinical trial.

Drug-induced toxicity in chronic alcoholics who participated in a 4-month placebo (Pl)--controlled clinical trial of the efficacy of calcium carbimide (CC) is reported. Daily monitoring of patients' compliance indicated that 85% of study medications were taken, and very little drinking took place during the study. Patients did not report more symptoms or experience more medical problems during CC administration than during placebo administration. There was no evidence of hepatotoxicity, or behavioural toxicity. Mean white blood cell count was slightly increased during CC treatment, and returned to baseline values when CC was stopped. Thyroid function was not affected by CC in patients with normal pretreatment function. However one patient with pretreatment reduced thyroid function became hypothyroid after CC administration, which indicates a need for systematic monitoring. We conclude that CC is safe for use in alcoholics with normal thyroid function, and may be the preferred alcohol-sensitizing drug in some situations.

A cognitive-social learning approach to relapse: pharmacotherapy and relapse prevention counselling.

A cognitive-social learning model of relapse prevention, specifically Albert Bandura's theory of self-efficacy, is one of the most influential theoretical frameworks that has been applied to the problem of relapse in the substance abuse field. Theory and research within this approach are reviewed and future directions for research are suggested. It is proposed that the critical distinction drawn between treatment strategies aimed at "initiation" versus "maintenance" of behaviour change provides a theoretical framework for the use of pharmacological agents in the treatment of alcohol problems. Pharmacological agents can be powerful in initiating a change in consumption, but if patients externally attribute to the drug the cause of their improvement, maintenance of improvement following withdrawal of the drug is likely to be poor. Relapse prevention counselling procedures, on the other hand, have been designed to provide self-attribution for change in drinking behaviour on the part of patients to promote maintenance of treatment effects. A combined approach using pharmacological agents (aimed at initiating a change in drinking) in conjunction with relapse prevention counselling procedures (aimed at fostering internal attribution and maintenance of change) should improve long-term outcome results. Available empirical evidence is presented.

The disulfiram (Antabuse)-Alcohol reaction in male alcoholics: its efficient management by 4-methylpyrazole.

4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, rapidly abolished the accumulation of acetaldehyde following alcohol ingestion both in volunteers pretreated with the Antabuse analog calcium carbimide and in an antabuse-treated alcoholic. 4-MP also attenuated other typical symptoms, including facial flushing and tachycardia, thus suggesting its usefulness in the acute treatment of severe disulfiram-alcohol reactions.

The use of calcium carbimide in relapse prevention counselling: results of a randomized controlled trial.

The effect of combining relapse prevention counselling with use of an alcohol-sensitizing drug was examined. Fifty-six alcoholic subjects who participated in a clinical trial of the short-acting alcohol sensitizing drug, citrated calcium carbimide, were randomly assigned to: (i) a Physician Advice condition in which subjects took the drug within a context designed to reinforce the medical management of their drinking problem; and (ii) a Relapse Prevention condition in which subjects were instructed to pair use of the drug with planned entry into high risk drinking situations and to gradually reduce reliance on the drug by developing alternative coping behaviour patterns. As predicted, subjects receiving carbimide in conjunction with relapse prevention counselling showed significant growth in internal attribution for change; whereas those receiving carbimide under more traditional medical management showed no movement toward internality. On measurement of alcohol consumption at 6, 12 and 18 months follow-up, there was some indication of superior maintenance of treatment gains at 18 months post-treatment for subjects who had received relapse prevention counselling, although the effect did not reach a conventional level of significance (F = 2.82; P less than 0.06). The findings are interpreted as consistent with a cognitive social-learning analysis of the maintenance of behaviour change.

Comparison of cyanamide and placebo in the treatment of alcohol dependence of adolescents.

AIMS: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that cyanamide may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term cyanamide treatment in alcohol dependence of adolescents. METHODS: In this, double-blind, placebo-controlled study, we recruited 26 patients, aged 16-19 years, with chronic (frequent and regular) or episodic (frequent, but irregular) alcohol dependence. Patients were randomly allocated treatment with cyanamide (200 mg daily) or a placebo for 90 days. Patients were assessed on the day the treatment was started, and on days 30 and 90, by interview, self-report, questionnaire and laboratory screening. Patients were classified as abstinent, relapsing or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. RESULTS: The cyanamide (n = 13) and placebo (n = 13) groups were well matched in terms of baseline demographic and alcohol-related variables. Mean cumulative abstinence duration was significantly greater in the cyanamide group than in the placebo group. Apart from occasional diarrhoea, there was no difference in side effects between groups. CONCLUSIONS: Cyanamide seems to be an effective and well tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for the treatment of some adolescent alcohol-dependent patients. Because of reported hepatotoxic, haematological and dermatological side effects, patients should be observed continuously by experienced clinicians. Further studies are necessary to prove the efficacy of cyanamide in adolescents.

A review of the clinical use of disulfiram and calcium carbimide in alcoholism treatment.

The role of disulfiram and calcium carbimide in alcoholism treatment is currently under critical review. Evidence supporting the efficacy of these drugs is unclear: although many alcoholism therapists are of the opinion that the alcohol deterrents are useful in the treatment of the chronic alcoholic, clinical studies with disulfiram that use proper evaluation methodologies report no or only low improvement rates, and there have been no controlled studies with calcium carbimide. Although disulfiram is thought to be safe when administered in therapeutic dosages, toxicity can occur in alcoholics treated with this drug. Information concerning the toxicity of calcium carbimide in alcoholics is incomplete. In this article, the efficacy and toxicity of disulfiram and calcium carbimide are reviewed, and guidelines for their safe and effective use in alcoholism treatment are presented.