Combined Efficacy of Acamprosate and Disulfiram in the Treatment of Alcoholism: A Controlled Study

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 380 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using χ², t , and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients ( p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 ( p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group ( p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.     

Evaluating the Efficacy of Closed-Loop Glucose Regulation via Control-Variability Grid Analysis

Background

Advancements in subcutaneous continuous glucose monitoring and subcutaneous insulin delivery are stimulating the development of a minimally invasive artificial pancreas that facilitates optimal glycemic regulation in diabetes. The key component of such a system is the blood glucose controller for which different design strategies have been investigated in the literature. In order to evaluate and compare the efficacy of the various algorithms, several performance indices have been proposed.

Methods

A new tool—control-variability grid analysis (CVGA)—for measuring the quality of closed-loop glucose control on a group of subjects is introduced. It is a method for visualization of the extreme glucose excursions caused by a control algorithm in a group of subjects, with each subject presented by one data point for any given observation period. A numeric assessment of the overall level of glucose regulation in the population is given by the summary outcome of the CVGA.

Results

It has been shown that CVGA has multiple uses: comparison of different patients over a given time period, of the same patient over different time periods, of different control laws, and of different tuning of the same controller on the same population.

Conclusions

Control-variability grid analysis provides a summary of the quality of glycemic regulation for a population of subjects and is complementary to measures such as area under the curve or low/high blood glucose indices, which characterize a single glucose trajectory for a single subject.     

Dose-Ranging Study of Depot Disulfiram in Alcohol Abusers

The object of this early Phase 2 study was to determine the dosage of depot disulfiram (DSF) required to induce sustained sensitivity to alcohol. Sixteen abstinent alcohol abusers were studied in an unblinded ascending-dose trial of DSF suspended in either (1) 5% methylcellulose or (2) 0.1% polysorbate 80. Five pairs of subjects received a single subcutaneous dose of Formulation A (1.0, 2.0, 2.5, 3.0, or 3.5 g). Three pairs were treated with Formulation B (60, 75, or 90 mg/kg) plus an oral loading dose of DSF (15 mg/kg). Subjects were challenged with oral alcohol (0.15 g/kg) before treatment, and on days 7, 14, 21, and 28. Subjective and objective responses to alcohol challenges (skin temperature, breath acetaldehyde, pulse rate, and blood pressure) were measured, and mobilization of DSF was assessed by carbon disulfide levels in breath. Treatment with Formulation B (75 or 90 mg/kg) plus an oral-loading dose (15 mg/kg) was consistently followed by sustained sensitivity to alcohol. Some subjects experienced the subjective and objective features of the DSF-ethanol reaction for 28 days, but these reactions achieved statistical significance only on day 7 for objective changes and on days 7 and 14 for subjective discomfort. Breath carbon disulfide was detectable until day 28 in all subjects receiving more than 1.0 g DSF, demonstrating sustained release of the drug. Treatment with depot DSF merits further study for its potential benefits in chronic alcohol abuse.     

纳洛酮联合醒脑静注射液治疗双硫仑样反应的临床疗效分析

目的分析纳洛酮联合醒脑静注射液治疗双硫仑样反应的临床疗效。方法选取2008年1月—2013年1月在我院就诊的双硫仑样反应患者341例,将其随机分为治疗组172例和对照组169例。对照组给予常规基础治疗,治疗组在对照组治疗基础上给予纳洛酮联合醒脑静注射液治疗。结果治疗组心绞痛样发作比例、症状缓解时间、总治疗时间及再住院率均低于对照组(P0.05)。结论纳洛酮联合醒脑静注射液治疗双硫仑样反应疗效显著,可显著降低心绞痛样发作比例、症状缓解时间、总治疗时间及再住院率。     

Life-Table Analysis of Treatment Outcome Following 185 Consecutive Alcoholism Halfway House Discharges

We define a halfway house as a transitional residence where patients learn skills and acquire confidence to function independently after discharge to a noninstitutionalized setting. Accordingly, our residents are provided shelter, food, counseling, group therapy, and medical care, but are expected to do assigned housework, attend AA, take disulfiram, obtain outside work, pay some rent, and find a place to live. The life-table method examines outcome for all patients seen up to the time of analysis and allows for different lengths of time that patients are known to the program. With this method, we calculated probability of not drinking ("survival") for successive 2-mo intervals after discharge from the house, based on the fate of all 185 patients known to us in August 1977. At least 101 patients drank during the first 2 mo. Cumulative probabilities of abstinence were 0.37 at 2 mo, 0.28 at 4 mo, 0.21 at 6 mo. and 0.19 for several months thereafter. Survival curves calculated for subsets of the population were similar when we classified for race, sex, prior inpatient rehabilitation, or employment at discharge. Patients older than 40 did slightly better. We conclude that (1) most patients will do well while in a sheltered environment, no matter what it is called, and (2) social rehabilitation itself does not produce sobriety. We will prevent relapses more effectively only when we better understand the physiology of alcohol hunger.     

A Community-Wide Study of Malaria Reduction: Evaluating Efficacy and User-Acceptance of a Low-Cost Repellent in Northern Ghana

NO MAS (NM) mosquito repellent was evaluated in two farming villages (4 km apart) in the Kassena Nankana district of northern Ghana. We determined its efficacy against local malaria vectors, degree of user acceptance, and its effect on malaria prevalence in households using insecticide-treated bed nets. The average protective efficacy of NM against Anopheles mosquitoes over 9 hours was 89.6%. Controls averaged 86 bites/person/night versus 9 bites/person/night with the use of NM. Use of repellent was associated with a decrease of absolute malaria prevalence by 19.2% in the repellent village and by 6.5% in the control village (45.5 to 26.3, and 29.5 to 23.0, respectively). The user-acceptance rate of NM repellent was 96.1%. Ten percent (10%) of repellent users reported irritation as the main adverse effect during the period. Eighty-five percent (85%) of the users found the odor of NM appealing and 87% reported no inconvenience in applying the repellent daily.     

A Double-blind Placebo Controlled Study of Male Alcoholics Given a Subcutaneous Disulfiram Implantation

Twenty-one alcoholics participated in a double blind study to elicit information of the clinical effect of implanted disulfiram. They were randomized to either of two groups, 11 patients to the placebo group and 10 patients to the disulfiram group. Each patient was subjected to seven sessions of intravenous ethanol challenge, once before and six times during the first 20 weeks after implantation. The acute ethanol challenge did not result in any differences between the groups with respect to blood ethanol and acetaldehyde concentrations. No patient showed any clinical signs of disulfiram-ethanol reaction. After a study period of 20 weeks no significant differences were found between the groups with regard to the reduction in average ethanol consumption, days from implantation to the first drink and number of abstinent weeks. Our results do not support the idea that a 1 g disulfiram implant has any pharmacological or clinical action.     

Chemical Monitoring of Disulfiram Compliance: A Study of Alcoholic Outpatients

Poor compliance with disulfiram (Antabuse) therapy may reduce its efficacy in the treatment of alcoholism. This study was designed to examine two questions: (a) Could use of a chemical test for disulfiram ingestion be used clinically to improve disulfiram compliance and if so, (b) could improved disulfiram compliance contribute to improved compliance with other aspects of treatment? The results suggest that disulfiram compliance rates can be increased by clinical use of chemical monitoring data; however in this sample increased compliance with disulfiram did not correlate with improvements in other aspects of treatment compliance.     

针灸疗效评价中盲法和安慰剂的选择

目的：针灸疗效评价中盲法和安慰剂选择是目前临床研究中的难点，针对此进行了探讨研究。方法：采用改进的Streitberger氏单盲法。56例病人随机分组，单盲法针灸治疗组(A组)和对照组(B组)治疗。间隔48h后，两组交叉进行治疗。用SPSS软件包进行数据统计学处理。结果：两次两组间年龄性别组成无统计学意义(P＞0.05)。两组间性别比较也无统计学意义(P＞0.05)。两组共336人次研究中，326人次(97．02％)均认为针灸针已穿透皮肤；318人次(94.64％)穿刺皮肤时有疼痛；“得气”者225人次(66．96％)。两次A组共168人次中117人次(69．64％)和B组168人次中108人次(64.29％)均有“得气感”。两组间比较无统计学意义(P＞0．05)。结论：改进后的Streit-berger氏单育法是一种较为可靠的、可行的单盲法。如果研究者不参与分组治疗过程，那么就可以做到双盲，进而就可以科学、公正地评价针灸疗效。     

MRI Study of Brain Changes with Short-Term Abstinence from Alcohol

Magnetic resonance brain scans were obtained from 10 chronic alcoholics within 2 weeks of alcohol withdrawal, and 19 to 28 days later. Age-matched control subjects were scanned at comparable intervals. At the initial scan, the alcoholics had larger lateral ventricles than the controls; at the second scan, their ventricles were significantly smaller than at the first scan. Among the controls, there was no mean change in the size of the lateral ventricles between the first and second scan. This study demonstrates reversibility in ventricular enlargement with short-term abstinence from alcohol. The role of rehydration in this process and the possibility of further changes with continued abstinence remain to be tested.     

A Randomized Controlled Study Evaluating the Safety and Efficacy of Deferiprone Treatment in Thalassemia Major Patients from Hong Kong

A controlled, open-label and randomized study was conducted to evaluate the safety and efficacy of the oral iron chelator deferiprone (L1) in thalassemia major patients from Hong Kong. Forty-nine patients were recruited in total (median age: 20 years; range: 8 to 40 years). The division of the patients was determined based on liver iron content and put into either the poorly-chelated (Group I) or well-chelated (Group II) groups. In Group I, 20 patients received combined therapy of L1 daily plus desferrioxamine (DFO), in a reduced frequency of twice weekly, while the control group consisted of 16 patients who were treated with DFO alone. In Group II, six patients received L1 only, while the control group consisted of seven patients treated with DFO alone. Only patients who participated for longer than 6 months were analyzed for efficacy (n = 44). The median study period was 18 months. Transient and mild gastrointestinal upset (31%), joint pain (15%) and liver enzyme elevation (23%) were the most common side effects noted for L1. No case of neutropenia was observed in this study. Serum ferritin (SF) levels showed significant decline in the poorly-chelated patients using combined therapy (L1 and reduced frequency DFO) as compared to those on DFO alone. However, their pre- and post-study liver iron content was not significantly different. Evaluation of the well-chelated group demonstrated no significant change in SF or liver iron content in both the study and control arms. We conclude that the short-term use of L1, with or without DFO, was safe and efficacious in our Chinese patient cohort. The long-term efficacy of reducing iron overload by treatment regimens including L1 requires further study.     

Disulfiram Therapy in Alcoholism: Patient Compliance Studied with a Urine-Detection Procedure

A simple urine test to verify disulfiram (Antabuse®) use has been developed. Compliance with disulfiram therapy was determined in 95 consecutive abstinent alcoholic patients in an outpatient clinic. All patients were allegedly taking disulfiram. Twenty percent of them were found not to be using the drug, even though they said they were. Disulfiram is unusual because it is probably the patient's belief that he is taking it that is therapeutic, not the action of the drug. Because of this, it is difficult to incorporate placebo controls and double-blind procedures into studies of disulfiram efficacy. However, with any research design, no conclusions will be valid if based solely on patients' reports of use.     

Evaluating the Safety and Efficacy of Silymarin in β-Thalassemia Patients: A Review

Abstract

β-Thalassemia (β-thal) is a type of hereditary anemia affecting hemoglobin (Hb) synthesis causing severe chronic anemia in homozygous patients. Regular blood transfusions are the mainstay treatment for this type of anemia. In turn, this leads to iron overload which is responsible for the formation of reactive oxygen species (ROS), oxidative stress and organ damage. Deferoxamine (DFO) is the standard of treatment for iron overload but regular painful subcutaneous administration of this medication prevents optimal compliance. Oral chelators, such as deferasirox (DFX) and deferiprone (DFP), are also effective and safe. Deferiprone is most effective in combination therapy with DFO rather than monotherapy; however, DFX is very expensive and the cost is a significant new burden for patients. Recently, researchers have proposed an iron chelating effect for silymarin that is a flavonoid extract from the milk thistle plant. This extract has different properties and has long been used for its antioxidant and hepatoprotective effects. In this review we assess different aspects of silymarin’s potential effects and compare them to the profile of thalassemic patients.     

Prognostic Validity of Short-Term Abstinence in Alcoholism

A demonstrated period of abstinence is often viewed as a good prognostic sign in alcoholism. For example, short-term abstinence one factor often considered important as a selection criteria for alcoholics who are being evaluated as liver transplant candidates. However, the prognostic validity of short-term abstinence is unclear. We evaluated the effects of 3 and 6 months of abstinence on readmission rates in a series of 299 alcoholics following discharge from inpatient treatment. Readmission rates were stratified using 3-factor model of alcoholism severity. This 3-factor model defined groups with 1-year readmission rates, ranging from 15.8% to 62.7%. Short-term abstinence did not have strong effects on readmission rates for the most severe alcoholics, nor did short-term abstinence produce clinically significant reduction for readmission rates for the least severe alcoholics. We conclude that short-term abstinence has minimal effect on prognosis for alcoholics with various levels of baseline severity.     

Liver Toxicity Encountered in the Veterans Administration Trial of Disulfiram in Alcoholics

Alcoholic subjects (453) were randomly assigned to disulfiram or placebo therapy and followed for up to 12 months for drinking. Drinking status was determined from interviews of the subject and a household contact each 2 months and from the analysis of eight blood samples or 39 urines submitted at intervals during the year. Liver status was monitored each 2 months by obtaining serum alkaline phosphatase, bilirubin, and AST. Sensitive criteria were arbitrarily selected to identify about 1/5 of the patients with episodic elevations of liver tests. There was no relationship of liver test elevations to disulfiram treatment. However, the elevated AST related significantly to drinking status (p = 0.004) as did elevated bilirubin (p = 0.044), but not elevated alkaline phosphatase (p = 0.146). Two hundred one patients had liver test elevations at least one time and were continued on drug, four were dropped. One hundred seventy-nine of these patients were drinking, 22 were abstinent, and four were indeterminant. It is concluded that patients on disulfiram with minor liver test abnormalities are usually drinking.