Arthur W.K. Chan

Detection by the CAGE of alcoholism or heavy drinking in primary care outpatients and the general population.

There is a need to improve the diagnosis of alcoholism in clinical settings because alcoholism, particularly in its early stages, is often unrecognized in general medical practice and in hospitals. In this study the CAGE questionnaire was used to detect alcoholism or heavy drinking in three populations, namely, alcoholics in treatment (ALC), primary-care outpatients (PC), and the general population (GP). Nearly all the ALC tested positive on the CAGE (97.8%), both for current (past year) and for lifetime alcohol-related problems. Among the PC subjects, 44.8% tested positive for lifetime alcohol problems, but the prevalence decreased to 17.2% when only past-year problems were considered. Likewise, 38.3% of the GP sample tested positive for lifetime, but half of these did not meet the 1-year recency criterion. Compared to DSM-III-R criteria during the same time intervals, the sensitivity/specificity of the lifetime CAGE was 91.2%/84.0% and 76.9%/85.1% in the PC and GP, respectively. The corresponding sensitivity/specificity of the past-year CAGE was 94.4%/97.0% and 74.6%/91.6%, respectively. Thus, the CAGE is an appropriate screening test for alcohol problems in these two populations, but other confirmatory tests or interviews are necessary to eliminate false positives. There were neither gender nor racial differences in the ALC sample responses to individual CAGE questions. However, there were gender differences in the PC and GP samples, with more males responding yes to each of the questions. The gender differences probably reflected the higher prevalence of heavy drinking and alcoholism among males.

Transferrin and mitochondrial aspartate aminotransferase in young adult alcoholics

Two recently proposed biochemical markers of alcoholism, namely, quantitation of plasma transferrin variant (Tf5.7) and the ratio of plasma mitochondrial aspartate aminotransferase (m-AspAT) to total AspAT (t-AspAT), were tested for their ability to detect young adult alcoholics. Another commonly used biochemical test, namely, activity of plasma gamma glutamyltransferase (GGT) was included as a comparison. Although mean values of GGT, TF5.7, total transferrin (Tftot), m-AspAT and t-AspAT in alcoholics were significantly higher than those in controls, there were too many overlapping values in each test between alcoholics and controls to render any of these tests suitable as a marker for young adult alcoholics. Depending on cut-off limits, the sensitivity of each test ranged from 0-52% and the specificity ranged from 80-97%. Moreover, the m-AspAT/t-AspAT and Tf5.7/Tftot ratios were not significantly different between alcoholics and controls. A stepwise linear discriminant function analysis of all the variables resulted in a slight increase in classification sensitivity (66%) but a decrease in specificity (77%). The relatively short duration (mean = 5.6 years) of heavy alcohol intake and the time elapsed (mean = 5.8 days) since the alcoholics last consumed alcohol very likely contributed to the low sensitivity. Young adults might also be more resilient with regard to the damaging biochemical effects of ethanol. Abnormal biochemical values might reverse to normal values much more quickly in young adult alcoholics than in those who are older and have more years of alcohol abuse.

Cross-tolerance between ethanol and chlordiazepoxide

Drug-induced hypothermia was used to investigate drug tolerance and cross-tolerance. C57BL/6J mice, which were injected with a single dose of chlordiazepoxide (CDP; 30 mg/kg) one day before and reinjected with an equivalent dose of CDP the next day, did not develop tolerance to the drug. However, ethanol-pretreated (3.5 g/kg, 24 hr earlier) mice, when injected with CDP (30 mg/kg), showed cross-tolerance to CDP. The cross-tolerance was short-lived (less than 48 hr). On the other hand, CDP-pretreated mice (30 mg/kg, 24 hr earlier) did not show cross-tolerance to ethanol. The lack of a reciprocating effect of CDP-pretreatment was not likely to be due to the difference in initial dosage between ethanol and CDP. It may be due to different rates of tolerance development or different mechanisms of actions between CDP and ethanol. Mice chronically treated with ethanol also showed a similar degree of cross-tolerance to CDP compared to those exposed to an acute dose of ethanol.

Differential effects of Ro15-1788 in actions of chlordiazepoxide and ethanol☆

Three behavioral tests, namely, runway activity, horizontal dowel test and hypothermia, were used to compare the effects of Ro15-1788, a specific benzodiazepine antagonist, on the common neuropharmacological actions of chlordiazepoxide (CDP) and ethanol in C57BL/6J mice. Ro15-1788 completely reversed the CDP-induced inhibition of runway activity and incoordination on a horizontal dowel, but only partially antagonized the hypothermic effects of CDP. The latter phenomenon was likely to be due to the rapid elimination of Ro15-1788, but could also be due to the fact that hypothermia might not be a specific action of CDP. The sedative actions of ethanol were not antagonized at all by Ro15-1788. In fact, Ro15-1788 potentiated the incoordinating effect of ethanol as determined by the horizontal dowel test such that mice injected with Ro15-1788/ethanol had lower brain ethanol levels than mice injected with vehicle/ethanol when they fell off the dowel. In contrast, mice injected with Ro15-1788/CDP took longer to fall off and had significantly higher CDP levels at fall-off than mice injected with vehicle/CDP. The stimulatory effect of a low dose of ethanol on runway activity was reversed by Ro15-1788. These data are discussed in terms of the possible mechanisms of actions for CDP and ethanol.

Does chronic ethanol intake confer full cross-tolerance to chlordiazepoxide?

Four behavioral tests, namely, hypothermia, horizontal dowel, runway and head-dipping, were used to assess tolerance to ethanol and cross-tolerance to chlordiazepoxide (CDP) in mice chronically treated with an ethanol diet for 15 days. Mice were tested on day 3 of ethanol withdrawal, with some being retested on day 8. In terms of hypothermia and the horizontal dowel test, ethanol tolerance conferred full cross-tolerance to CDP, but the conclusion based on results of the latter test may be equivocal. Partial cross-tolerance to CDP was observed in the runway test, while no cross-tolerance to CDP was detected in the head-dipping test. For these latter two tests ethanol tolerance was present in the mice. Thus, the degree of equivalence between tolerance to ethanol and cross-tolerance to CDP in ethanol-dependent mice varied with the behavioral tests to assess tolerance. Possible mechanisms are discussed.

Identification of Alcoholism in Young Adults by Blood Chemistries

A stepwise linear discriminant analysis was conducted between young adult alcoholics in an alcoholism treatment center and non-alcoholic college students. Analysis of 31 commonly ordered clinical laboratory tests yielded three significant variables (urea nitrogen, potassium and MCV) which correctly classify 89% of alcoholics and 92% of non-alcoholics.

The Optimal Temperature for Preservation of the Myocardium during Global Ischemia

To determine the myocardial temperature that provides maximal preservation of the heart during global ischemic arrest, five groups of dogs were studied (6 per group). In all animals, the aorta was cross-clamped for 120 minutes. Serial biopsies were done for determination of adenosine triphosphate and creatine phosphate, and study by electron microscopy. Starling curves were derived prior to cardiopulmonary bypass and 60 minutes after bypass. Mitochondrial changes were graded on a scale of 0 to 4. In the control group (Group 1), the aorta was clamped when the rectal temperature reached 25 degrees C (myocardial temperature, 18 degrees to 22 degrees C). In Groups 2, 3, 4, and 5, myocardial temperature was maintained at 6 degrees C, 10 degrees C, 14 degrees C, and 18 degrees C (all +/- 2 degrees C), respectively, by the use of systemic and topical hypothermia and repeated injections of cold cardioplegic solution into the aortic root. All groups showed a depression of left ventricular stroke work index, particularly Group 1 (no survivors), Group 2, and Group 3. The high-energy phosphate stores were well preserved in all groups except Group 1. The mitochondrial ultrastructure showed significant changes in all groups, especially Groups 1 and 5. These data indicate that satisfactory preservation of mitochondrial ultrastructure and high-energy phosphates was achieved at myocardial temperatures lower than 18 degrees C. Extreme hypothermia (Groups 2 and 3) was associated with significant reduction in ventricular function under the experimental conditions employed.

Substitution of chlordiazepoxide for ethanol in alcohol-dependent mice☆

Alcohol dependence was induced in C57BL/6J mice by administration of a liquid diet containing ethanol. These mice showed alcohol withdrawal signs when the alcohol diet was withdrawn. However, when the alcohol diet was substituted with three liquid diets containing different amounts of chlordiazepoxide (CDP; 0.4, 1 and 2 mg/ml), the alcohol withdrawal signs were fully suppressed by CDP. The CDP diet administration was continued for 14-24 days. At termination of the diet treatment, the mice showed CDP withdrawal signs. Similar signs, but much more short-lived, can be precipitated by injection of the benzodiazepine receptor antagonist, RO-15-1788. The results are consistent with the hypothesis that alcohol-dependent mice are cross-dependent on CDP. This report constitutes the first experimental demonstration of cross-dependence between ethanol and CDP. The reverse phenomenon, namely, CDP-dependent mice being cross-dependent on ethanol, remains to be investigated.

Flumazenil (Ro15-1788) does not affect ethanol tolerance and dependence.

There are conflicting reports concerning whether flumazenil (Ro15-1788) can antagonize the central effects of ethanol and ethanol withdrawal reactions. C57BL/6J mice were treated chronically with an ethanol liquid diet. Control mice were pair fed an isocaloric diet containing no ethanol. These mice were injected with either Ro15-1788 (25 mg/kg) or vehicle immediately before, 14 h or 24 h before ethanol withdrawal. Under these conditions, no attenuation of the severity of handling-induced withdrawal seizures or of withdrawal hypothermia was observed in the ethanol-dependent mice injected with Ro15-1788. Likewise, there was no abolition or attenuation of tolerance to the ataxic effects (sleep time and horizontal dowel tests) and hypothermic effects of ethanol by Ro15-1788 when the mice were tested on day 3 of ethanol withdrawal. It is concluded that Ro15-1788 (25 mg/kg) has no effect on ethanol tolerance and dependence.

Relationship of brain cyclic nucleotide levels and the interaction of ethanol with chlordiazepoxide

The effects of combined administration of ethanol (4 g/kg) and chlordiazepoxide (CDP, 12.5 mg/kg) on mouse brain c-AMP and c-GMP levels were investigated in order to test the hypothesis that the supra-additive effect of CDP on ethanol sleep time may be related to a supra-additive alteration in brain cyclic nucleotide levels induced by the combined drugs. Ethanol alone or CDP by itself did not cause any change in brain c-AMP levels, except for a transient decrease in the cerebral cortex and midbrain at 0.5 hr after ethanol injection, as well as a transient increase in the cerebellum at 0.5 hr after CDP injection. The combined drug treatment did not result in a supra-additive effect on c-AMP levels. On the other hand, c-GMP levels were depressed significantly for 4 hr after ethanol injection especially in the cerebellum. The mice regained the righting reflex when the c-GMP levels were still about 30 per cent of control values. Ethanol and CDP together induced a supra-additive decrease of c-GMP concentrations in the cerebellum at 2 and 4 hr. This resulted in a lengthened period (about 2.5 hr) during which the cerebellar c-GMP levels were below 30 per cent of control values, and this interval coincided with the increase in sleep time, suggesting a possible relationship between these two factors. Injection of ethanol and N-demethyl-chlordiazepoxide (NDCDP) simultaneously (the latter being a metabolite of CDP) also elicited a more than additive depression of cerebellar c-GMP levels at 4 hr. These data suggest that NDCDP or its metabolite could be responsible for the supra-additive effect of CDP on the ethanol-induced decrease in cerebellar c-GMP levels.