Chronic ethanol abuse and membrane fluidity changes in liver disease.

The long-term effect of ethanol on human red cell membrane fluidity was studied, by fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene as a probe, in 11 healthy subjects, 9 chronic alcoholics without evidence of liver disease, 12 chronic alcoholics with biopsy-proven alcoholic liver disease and 9 abstemious patients with chronic active liver disease, most of them cirrhosis of the liver. Fluorescence polarization values were not significantly different in the two groups without liver disease. Patients with alcoholic and non-alcoholic liver disease showed higher fluorescence polarization values than patients without liver disease. These changes correlated with the severity of liver dysfunction and were not related to alcohol consumption. In conclusion, the decrease in fluidity of the erythrocyte membrane in alcoholic patients with chronic liver disease, is related to liver dysfunction but not to chronic ethanol ingestion. Changes in membrane fluidity in chronic alcoholics are found only in the presence of liver disease.     

Dexamethasone suppression test in recently detoxified alcoholics: clinical implications

An overnight dexamethasone suppression test (DST) was performed on 66 nondepressed primary alcoholics, a mean of 20.79 +/- 11.5 days after last alcohol intake. The Beck Depression Inventory (BDI) was given concurrently. Only 6% of the subjects were nonsuppressors. There was no correlation between cortisol levels at 17 and 24 hours postdexamethasone and the age of the subjects or duration of abstinence. There was a low level correlation between cortisol values at 24 hours and the BDI scores. Review of published data indicates that the DST may be abnormal in alcoholics in the first 2 weeks of abstinence, probably a result of abnormal liver function and withdrawal phenomena. DST response of alcoholics resembles that of normal controls after more than 2 weeks of abstinence. Alcoholics with clinical features of depression and an abnormal DST after 2 weeks of abstinence may be candidates for antidepressant therapy or electroconvulsive therapy.     

Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake

Abstract: Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison to healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol-free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N-demethyl-diazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15% in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N-demethyldiazepam.     

Alcohol and bupropion pharmacokinetics in healthy male volunteers

Summary A study was performed to determine whether there is a pharmacokinetic interaction between alcohol and the novel antidepressant bupropion. In the first part 8 healthy male volunteers received single doses of 100 mg bupropion hydrochloride orally on 2 occasions accompanied by either ethanol in orange or plain orange drink according to a balanced cross over design. Plasma bupropion concentrations were determined by radioimmunoassay and kinetics analysed with the aid of NONLIN. Blood alcohol levels were assessed by breathalyser. The disposition of bupropion was adequately described by a 2 compartment model and kinetic parameters were not significantly altered by the presence of alcohol. In the second part of the study the same subjects received 40 ml ethanol in orange drink 3.5 h after ingestion of 100 mg bupropion or dummy tablet in a double blind cross over fashion. Bupropion did not affect alcohol kinetics. In contrast to many other psychotropic drugs there is no evidence for a kinetic interaction between bupropion and alcohol.     

The effects of chronic alcohol ingestion and alcoholic liver disease on binding of drugs to serum proteins

Summary The binding of salicylate, sulphadiazine and phenylbutazone in whole serum of patients with alcohol-induced liver disease has been compared to that of chronic alcoholics with no evidence of liver disease, and normal healthy subjects. Binding of all three drugs was normal in the chronic alcoholic group, but decreased in patients with alcoholic liver disease. In subjects with alcoholic hepatitis, this decrease appeared to be correlated with variations in serum bilirubin and albumin levels. These observations may be of clinical relevance to the distribution of drugs in alcoholic patients with accompanying hepatic disease.     

Influence of food on tianeptine and its main metabolite kinetics

The influence of a test meal on the absorption and disposition of tianeptine (Stablon), a new antidepressant, was investigated in 12 healthy subjects in a two-way, randomized, open cross-over study. Single 12.5-mg oral doses of tianeptine were administered following a night of fasting or immediately after a standardized breakfast. When subjects received tianeptine under fasting conditions the lag time before absorption onset, and the time of the maximum plasma concentration were 0.55 +/- 0.26 hours and 1.29 +/- 0.29 hours, respectively. The maximum plasma concentration was 322 +/- 44 ng/mL, and the total area under the curve 994 +/- 248 ng/hr/mL. When tianeptine was given at the end of the meal, several significant changes were found for tianeptine kinetic parameters; the lag time increased by 0.3 hour and the maximum plasma concentration was lowered (decreased by 25%) and occurred later (tmax increased by 0.5 hour). However, no significant change was found in the area under the plasma concentration-time curve. The trend and extent of changes in the MC5 metabolite parameters were similar to those observed for the parent drug. Absorption of tianeptine is slightly delayed and slowed down without modification of its extent when tianeptine is given at the end of a meal. These slight changes are not clinically relevant for an antidepressant administered three times a day. Despite the changes observed, tianeptine may be given at meal times to improve compliance with treatment.     

Increased prolactin reserve in alcoholics

The prolactin response to oral metoclopramide (10 mg) was investigated in 53 chronic alcoholics (26 with alcoholic cirrhosis and 27 without evidence of liver disease) from two to seven days after alcohol suspension. The response appeared significantly higher in patients than in healthy controls and was not related to the presence of liver disease. This finding may depend on the deactivation of the dopaminergic activities secondary to alcohol suspension; alternatively, ethanol could have a direct action on prolactin secretion.     

Alprazolam pharmacokinetics in alcoholic liver disease

Alprazolam, a triazolobenzodiazepine, was administered to 17 patients with alcoholic liver disease. The pharmacokinetic parameters derived from plasma alprazolam concentrations were compared with data obtained from 17 normal subjects who were matched for age and sex. The rate of absorption of alprazolam was slower in patients with alcoholic liver disease. The time of maximum serum concentration was 3.3 hours, compared with 1.5 hour in normals (P less than 0.02). The maximum concentrations, however, did not differ (18.4 vs. 17.2 micrograms/ml). The elimination half-life of drug was longer in the patients (19.7 hours) than in the normal subjects (11.4 hours), while the clearance of the drug was slower in the patients with alcoholic liver disease (0.6 vs 1.2 ml/min/kg). The volumes of distribution (area) did not differ between the two groups (1.1 vs. 1.2 liter/kg). The changes in elimination half-life and clearance indicate that the metabolism of the drug is slowed in patients with alcoholic liver disease.     

Degrees of alcohol intoxication in 117 hospitalized cases

The correlation among degrees of alcohol intoxication, facial flushing, blood alcohol concentration (BAC) and blood acetaldehyde level was studied in 117 male alcoholic patients who underwent various tests to assess alcohol influence. Blood samples were collected and alcohol and acetaldehyde levels were determined. BACs ranged from 29 to 577 mg/dl in all patients and from 200 to 299 mg/dl in 48 of them. Fifty-one patients could stand erect (mean BAC [+/- SD] = 189 +/- 80 mg/dl), while 48 showed apparently normal reaction to a walking and turning test (mean BAC = 192 +/- 78 mg/dl). Some of the cases having BACs over 300 mg/dl could still stand and walk while others with BACs under 100 mg/dl already showed psychomotor impairment. Facial flushing was recognized in 75% of the subjects. Acetaldehyde concentrations in 27 patients ranged from 24 to 147 micrograms/dl. Appearance of facial flushing was correlated with relatively high concentrations of blood acetaldehyde. Seven out of 10 healthy volunteers given 1.6 to 2.0 g/kg of alcohol as a control could do nothing but sleep after reaching peak BAC (mean = 232 +/- 21 mg/dl). These findings are taken to indicate a great difference in response to alcohol between alcoholics and healthy men. This study is the first to report the occurrence of facial flushing and raised blood acetaldehyde concentration among Japanese alcoholics.     

Chlorpropamide 2-hydroxylation is catalysed by CYP2C9 and CYP2C19 in vitro: chlorpropamide disposition is influenced by CYP2C9, but not by CYP2C19 genetic polymorphism

AIMS: We evaluated the involvement of cytochrome P450 (CYP) isoforms 2C9 and 2C19 in chlorpropamide 2-hydroxylation in vitro and in chlorpropamide disposition in vivo. METHODS: To identify CYP isoforms(s) that catalyse 2-hydroxylation of chlorpropamide, the incubation studies were conducted using human liver microsomes and recombinant CYP isoforms. To evaluate whether genetic polymorphisms of CYP2C9 and/or CYP2C19 influence the disposition of chlorpropamide, a single oral dose of 250 mg chlorpropamide was administered to 21 healthy subjects pregenotyped for CYP2C9 and CYP2C19. RESULTS: In human liver microsomal incubation studies, the formation of 2-hydroxychlorpropamide (2-OH-chlorpropamide), a major chlorpropamide metabolite in human, has been best described by a one-enzyme model with estimated K(m) and V(max) of 121.7 +/- 19.9 microm and 16.1 +/- 5.0 pmol min(-1) mg(-1) protein, respectively. In incubation studies using human recombinant CYP isoforms, however, 2-OH-chlorpropamide was formed by both CYP2C9 and CYP2C19 with similar intrinsic clearances (CYP2C9 vs. CYP2C19: 0.26 vs. 0.22 microl min(-1) nmol(-1) protein). Formation of 2-OH-chlorpropamide in human liver microsomes was significantly inhibited by sulfaphenazole, but not by S-mephenytoin, ketoconazole, quinidine, or furafylline. In in vivo clinical trials, eight subjects with the CYP2C9*1/*3 genotype exhibited significantly lower nonrenal clearance [*1/*3 vs.*1/*1: 1.8 +/- 0.2 vs. 2.4 +/- 0.1 ml h(-1) kg(-1), P < 0.05; 95% confidence interval (CI) on the difference 0.2, 1.0] and higher metabolic ratios (of chlorpropamide/2-OH-chlorpropamide in urine: *1/*3 vs.*1/*1: 1.01 +/- 0.19 vs. 0.56 +/- 0.08, P < 0.05; 95% CI on the difference - 0.9, - 0.1) than did 13 subjects with CYP2C9*1/*1 genotype. In contrast, no differences in chlorpropamide pharmacokinetics were observed for subjects with the CYP2C19 extensive metabolizer vs. poor metabolizer genotypes. CONCLUSIONS: These results suggest that chlorpropamide disposition is principally determined by CYP2C9 activity in vivo, although both CYP2C9 and CYP2C19 have a catalysing activity of chlorpropamide 2-hydroxylation pathway.     

The effects of a beta-2 selective adrenergic agonist and a beta-nonselective antagonist on theophylline clearance

Beta-adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 +/- 12.9 vs 40.6 +/- 9.9 mL/min/1.73m2; P less than .01) increased half-life (8.37 +/- 1.77 vs 12.32 +/- 2.70 hours; P less than .05), and increased postinfusion theophylline concentration (13.5 +/- 2.7 vs 18.95 +/- 2.5 micrograms/mL; P less than .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 +/- 13.0 vs 75.0 +/- 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 +/- 12.7 vs 36.1 +/- 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta-2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta-adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

Quinidine disposition in relation to antipyrine elimination and debrisoquine phenotype in alcoholic patients with and without cirrhosis

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.     

No evidence of a genetic polymorphism in the oxidative metabolism of midazolam

The benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t1/2) is about 2.4 hours. A recent study showed a prolonged t1/2 from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam's metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (alpha-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and alpha-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 +/- 961 x 10(5) h/ml; mean +/- SD) and for the metabolic plasma ratio (AUC of alpha-OH-midazolam/AUC-midazolam: 0.52 +/- 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 +/- 2.4%), urinary excretion of alpha-OH-midazolam (55.9 +/- 22.7% of dose) and the values for t1/2 (2.9 +/- 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p less than 0.05) metabolic ratio. Only in 3 patients could a prolonged t1/2 of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of alpha-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.     

Drinking patterns and beverage preferences of liver cirrhosis patients in Mexico

The purpose of this study was to investigate the pattern of alcoholism in a special group of alcoholics (alcoholic cirrhotics) in a hospital-based population in west central Mexico and assess the role of regional spirits such as tequila. A complete alcohol drinking history and a structured questionnaire directed at investigating the pattern of alcohol consumption was applied to 124 adult patients with chronic liver disease caused by alcohol during January 1995 to January 1996. The mean age of onset was 27 +/- 3 years in women and 18 +/- 0.5 years in men. The mean alcohol intake per week was 749 +/- 192 g for women and 1113 +/- 151 g for men. On average, patients consumed alcohol for a mean of 24.5 years. The overall patient drinking preference was for tequila followed by 96 degree Gay Lusac (G.L.), alcohol, and beer. In a subset of 70 patients three phases of alcoholism could be identified (prealcoholic, critical, and chronic). Each phase had a mean duration of at least 11 years. Beer was the dominant beverage in the prealcoholic phase while tequila was consumed more often in the other phases. In the critical phase of alcoholism an average of 337 g of alcohol were consumed per week and in the chronic phase 1765 g/week. Tequila was the overall preferred beverage in this group of alcoholics. Other beverages included beer and straight alcohol with a clear trend from less to higher concentration of alcohol throughout the drinking history. Subtle gender differences in the patterns of alcoholism may be suspected. In this group of patients the role of tequila drinking is highlighted.     

Intravenous pharmacokinetics of 2-hydroxyimipramine in alcoholics and normal controls

Fifteen subjects (seven recently abstinent, male, chronic alcoholics and eight, age- and weight-matched male controls) were administered 10 mg 2-hydroxyimipramine (2-OHIMI) by intravenous infusion. Pharmacokinetic parameters were determined from multiple blood samples drawn over 60 hours. Total body clearance of unbound drug, as calculated from the plasma concentration versus time data, was significantly increased in the alcoholic group as compared to the control group (3.12 vs 1.51 L/hr/kg). Terminal elimination half-life was decreased in the alcoholics (7.07 vs 10.12 hr). The fraction of the drug unbound to plasma protein was determined by equilibrium dialysis and was found to be decreased in the alcoholic group over that found in the controls (29.8 vs 36.4%). All subjects were monitored by EKG during the first 4 hours of sampling. Although there was a small mean decrease in heart rate following infusion, it did not achieve statistical significance. Alcoholics had a greater mean increase in P-R but not QTc intervals than control subjects, a difference that was significant at 45 minutes and 1 hour postinfusion. There were no significant differences in the percentage of subjects with abnormal P-R or QTc intervals between the alcoholic and control groups.     

Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment

Levosimendan is a vasodilator used in the treatment of acute heart failure. In the present study, the effect of hepatic impairment on the pharmacokinetics of levosimendan and its 2 metabolites, OR-1855 and OR-1896 (pharmacologically active), was investigated in 12 healthy subjects and 12 subjects with moderate hepatic impairment due to alcoholic cirrhosis of the liver but with no heart failure. In addition, the effect of acetylator status on the pharmacokinetics of levosimendan, OR-1855, and OR-1896 was evaluated. Safety and tolerability of levosimendan were also assessed. Levosimendan was given as an intravenous infusion of 0.1 microg/kg/min for 24 hours. Levosimendan showed similar C(max), AUC, and elimination half-life (t(1/2)), with a mean (+/-SEM) t(1/2) of 0.9 +/- 0.0 hours in healthy subjects and 0.8 +/- 0.1 hours in hepatically impaired subjects, respectively (not significant). The t(1/2) of OR-1855 was 61 +/- 5 hours in healthy subjects and 82 +/- 3 hours (P < .01) in subjects with hepatic impairment. The t(1/2) of OR-1896 was 62 +/- 5 hours and 91 +/- 5 hours (P < .01), respectively. However, the AUCs of OR-1855 and OR-1896 were similar in healthy volunteers and hepatically impaired subjects. The effect of acetylator status was seen as higher C(max) and AUC of OR-1855 in slow acetylators. Correspondingly, higher C(max) and AUC of OR-1896 were observed in rapid acetylators. Levosimendan was well tolerated in both study groups. In conclusion, the pharmacokinetics of the parent drug levosimendan was unaltered in subjects with moderate hepatic impairment, whereas the elimination of the metabolites was prolonged. However, because the maximum duration of levosimendan infusion is 24 hours, dosing adjustments of levosimendan may not be required in subjects with impaired hepatic function.     

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (-76%, P < 0.05). This was due primarily to a lower portal vein blood flow (-36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean +/- s.d.-healthy controls: t1/2 = 13.7 +/- 3.0 h, CL = 30.0 +/- 8.6 ml h-1 kg-1, AUC = 549 +/- 139 mg l-1 h; cirrhotic patients: t1/2 = 32.4 +/- 1.7 h, CL = 12.3 +/- 2.1 ml h-1 kg-1, AUC = 1061 +/- 218 mg l-1 h; P < 0.008). Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: t1/2 = 14.3 +/- 3.7 h, CL = 29.3 +/- 8.5 ml h-1 kg-1, AUC = 498 +/- 142 mg l-1 h). The volume of distribution of antipyrine was similar in all three groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of zimeldine in male alcoholics

The pharmacokinetics of zimeldine, a 5-HT reuptake blocker with antidepressive effects, was studied after a single oral dose and after multiple oral administration in 19 alcoholic males, 10 with and 9 without chronic liver damage. The average plasma concentration of zimeldine as assessed by the AUC values (area under the plasma concentration-time curve) was significantly higher in the chronically liver damaged patients than in the patients without chronic liver damage. The plasma half-life of zimeldine was also significantly longer in the chronically liver damaged patients. There were no differences in the obtained pharmacokinetic parameters between the patients having nonchronic liver damage and healthy control subjects. The pharmacokinetics of the active metabolite norzimeldine (resulting from N-demethylation of zimeldine) showed no differences between the two groups of alcoholics and the healthy controls. The IgA values were significantly correlated to both the AUC and plasma half-life of zimeldine. No other correlation between clinical chemistry parameters and pharmacokinetic parameters of zimeldine and norzimeldine were found.     

Verbal and nonverbal abstracting--problem-solving abilities and familial alcoholism in female alcoholics

Women alcoholics (N = 54) had significantly worse performance on clusters of verbal and nonverbal abstracting - problem-solving tasks than peer nonalcoholic controls (N = 48). On the nonverbal cluster, alcoholic women with an alcoholic parent or sibling (FH+) performed significantly poorer than peer alcoholics without such a family history (FH-) and nonalcoholic FH+ and FH- groups. On the verbal cluster, FH+ alcoholics performed significantly worse than the nonalcoholic groups. FH- alcoholics did not differ significantly from the nonalcoholic groups on either of the clusters. There were no differences between FH+ and FH- nonalcoholics on the two types of tasks. The results suggest that female alcoholics have a generalized deficit on cognitive tasks involving abstracting and problem-solving, and that these deficits tend to be more pronounced in alcoholic women with a positive family history of alcohol abuse. Whether these deficits are due to a premorbid lowering of abstracting - problem-solving abilities in the FH+ individuals who subsequently become alcoholics, or are the result of a selective vulnerability of these cognitive processes to the effects of alcohol abuse in such subjects, or some combination of these factors, remains to be investigated.