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C A Naranjo

Publications and source records attributed to C A Naranjo.

At least 19 recordsLinked to original sources
PubMed1992

Advances in the diagnosis of adverse drug reactions.

The clinician plays a key role in the detection and diagnosis of adverse drug reactions (ADRs). The diagnosis of ADRs, however, is a complex task. In the past, there were no systematically applied diagnostic criteria for ADRs, no formal methods of case analysis, no standardized epidemiologic approaches, and a limited knowledge of mechanisms. This resulted in the overdiagnosis of ADRs, which has negative consequences such as limiting treatment options. Recently, there have been various improvements in the diagnosis of ADRs, such as the development of standardized decision aids and of in vitro diagnostic tests. This article briefly reviews some of this knowledge, discusses the role of in vivo and in vitro rechallenge, and summarizes a probabilistic approach for collecting relevant information and diagnosing ADRs. The intention is to increase awareness of the different approaches for diagnosing ADRs as well as to stimulate researchers to continue to collect pharmacoepidemiologic information, study the pharmacologic, immunologic, and genetic factors involved in the pathogenesis of drug reactions, and develop and test new diagnostic instruments under various clinical conditions.

Adverse Drug Reaction Reporting Systems↗
PubMed1992

Citalopram decreases desirability, liking, and consumption of alcohol in alcohol-dependent drinkers.

In previous studies serotonin uptake inhibitors such as citalopram decreased alcohol consumption in alcoholics. The mechanism of the effect is not fully understood. This study tested the hypothesis that it is mediated by changes in desire to drink and alcohol effects. After a 1-week baseline period, subjects (13 men and three women; aged 26 to 69 years; healthy, nondepressed, alcohol-dependent drinkers [mean, 6.6 drinks per day]) were randomized in a double-blind fashion to receive 40 mg/day citalopram and placebo for 1 week each, separated by a 1-week washout period. Daily standard alcoholic drinks (13.6 gm ethanol), nonalcoholic drinks, and tobacco use were recorded; evening urine samples were taken; and interest, desire, craving, and liking for alcohol were rated. Medical status, depression, and anxiety were assessed weekly, but no other treatment or advice was given. Daily alcoholic drinks significantly decreased during citalopram treatment (mean +/- SEM = 4.6 +/- 0.6) compared with placebo (5.7 +/- 0.8; p = 0.01), and the average decrease was 17.5%. Percentage of days abstinent increased during citalopram administration (27.7% +/- 5.7%) compared with placebo (15.5% +/- 3.7%; p less than 0.01). Citalopram decreased interest, desire, craving, and liking for alcohol (all p less than 0.05). There was clear internal validation of these measures in that variations in each correlated with alcohol consumption (all r greater than 0.5, p less than 0.05). Nonalcoholic drinks, self-reports of cigarettes smoked (daily smokers), and body weight did not change significantly. In experimental bar sessions, after the citalopram and placebo periods, subjects were required to consume as many of 18 minidrinks as possible (equivalent to six standard drinks) at 5-minute intervals. Subjects rated their desire for alcohol, intoxication, and mood. Citalopram had no significant effects on the desirability of alcohol or subjective feelings of intoxication. The findings indicate that serotonin uptake inhibitors may act by decreasing the urge to drink and the reinforcing effects of alcohol. Also, a naturalistic outpatient trial is a sensitive, simple, and economic procedure for detecting these drug effects.

Adult↗
PubMed1992

Eating disorders and alcohol abuse in women.

Theory and empirical evidence support a relationship between the eating disorders (anorexia nervosa and bulimia nervosa) and alcoholism. This study examines the co-prevalence and characteristics of these disorders among two populations of adult women: those presenting for treatment of alcoholism and those referred to a specialized eating disorders programme. Twenty-two of 73 females (30.1%) with alcohol problems met psychometric cut-off scores for eating disorder, while 25 of the 96 eating disorder females (26.9%) gave psychometric evidence of alcohol dependence. These rates exceed general population norms. While certain clinical and psychometric features distinguish subgroups with both disorders, the basis for co-prevalence and the implications for treatment are unknown.

Adult↗
PubMed1991

Enalapril effects on alcohol intake and other consummatory behaviors in alcoholics.

Animal studies suggest that angiotensin-converting enzyme inhibitors decrease alcohol intake. In a double-blind crossover study 42 normotensive alcoholics (36 men and six women) aged 24 to 65 years, consuming 8.2 +/- 2.3 (mean +/- SD) standard alcoholic drinks per day, were randomized to enalapril, 10 mg/day (n = 20) or 20 mg/day (n = 22), and placebo for 4 weeks. They monitored their daily alcohol intake and attended biweekly assessments, but no other treatment or advice was given. Compliance and alcohol intake were verified objectively. Mean daily alcoholic drinks were not significantly different during 10 mg/day enalapril (mean +/- SEM, 7.5 +/- 0.5), and its placebo (7.2 +/- 0.5), but both decreased from baseline (8.1 +/- 0.5; both p less than 0.05). Similarly, mean daily drinks during 20 mg/day enalapril (6.8 +/- 0.6) and its placebo (7.2 +/- 0.4) was not significantly different, but both were lower than baseline (8.3 +/- 0.5; both p less than 0.01). Fourteen (64%) of the patients taking 20 mg/day enalapril decreased alcohol intake from placebo by an average of 21% (range, 1.6% to 78.3%). Self-ratings of interest, desire, craving, and liking for alcohol also decreased from baseline during enalapril and placebo treatments, but the effects of both were similar. Plasma renin activity increased, compared with placebo, after 10 mg/day enalapril (from 0.3 +/- 0.2 [mean +/- SD] to 1.9 +/- 1.5 ng/L/sec) and after 20 mg/day enalapril (from 0.4 +/- 0.3 to 2.8 +/- 4.0 ng/L/sec) (both p less than 0.05). Blood pressure decreased within a normotensive range, compared with placebo, with 10 mg/day enalapril (by 6.0 and 8.5 mm Hg systolic and diastolic blood pressures) and 20 mg/day enalapril (by 7.7 and 5.0 mm Hg, respectively). Side effects were few and mild. No patient characteristic or drug effect correlated with changes in alcohol intake. There were no significant variations in nonalcoholic beverages, cigarette smoking, or body weight. These results indicate that enalapril does not alter alcohol intake in normotensive alcoholics with normal plasma renin activity. Studies with higher doses of enalapril in humans may be limited by increased frequency and severity of side effects.

Adult↗
PubMed1991

Endogenous opioids are involved in the genetically determined high preference for ethanol consumption.

The link between endogenous opioid peptides and the genetic predisposition to preferentially consume ethanol was examined in alcohol preferring C57BL/6J mice compared with the alcohol nonpreferring DBA/2 mice. Concentrations of Met-enkephalin pentapeptide or precursor in various brain regions of potential relevance were not different between the two strains. C57BL/6J mice had a significantly lower pain threshold that could be increased by a selective mu-receptor opioid agonist [D-Ala2, MePhe4, Met(O)5-ol]-enkephalin. Treatment with this drug also decreased ethanol consumption in C57BL/6J mice. Increasing the synaptic half-life of endogenous enkephalins by the enkephalinase inhibitor kelatorphan also decreased ethanol consumption. Assay of endogenous enkephalin degrading activity showed increased enkephalinase activity in striatal issue of C57BL/6J compared with DBA/2 tissue. These results suggest that a relative lack of enkephalin peptides trans-synaptically, possibly resulting from enhanced enkephalin degradation may contribute to increase alcohol consumption in C57BL/6J mice.

Alcohol Drinking↗
PubMed1991

Possible pharmacological probes for predicting and preventing relapse in treated alcoholics.

Relapse is a frequent problem for recovered alcoholics since up to 80% do so within 6 months of completing treatment. Although the mechanisms underlying relapse are unknown, several internal and external cues have been associated with it. Desire (or craving) for alcohol is an internal cue which may precipitate relapse and is amenable to physiological and pharmacological studies. Recent studies have indicated that pharmacological manipulations of the serotonergic system can produce variations in craving for alcohol. For example, when challenged with the putative serotonin1 (5-HT1) agonist, m-chlorophenylpiperazine (m-CPP), alcoholics report increases in craving and desire for alcohol (George et al, 1990). In our studies with moderately dependent alcoholics, 5-HT uptake inhibitors (e.g., citalopram) reduced both the craving for and the consumption of alcohol. Studies are underway to identify the mechanism underlying these findings. Other systems may also regulate alcohol craving. However, some agents which allegedly decreased alcohol intake in animals, such as enalapril, an angiotensin converting enzyme inhibitor, showed no effect on desire for or intake of alcohol in humans. A better understanding of the neural and systemic mechanisms underlying alcohol craving may help us in the prediction and/or prevention of relapse in treated alcoholics.

Alcohol Drinking↗
PubMed1990

Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers.

The effects of fluoxetine, a relatively selective long-acting serotonin uptake inhibitor, on the consumption of alcoholic and nonalcoholic drinks, cigarette smoking, and body weight were assessed in 29 men who were early stage problem drinkers. After a 2-week baseline, subjects were randomly assigned to receive 40 mg/day fluoxetine (n = 8), 60 mg/day fluoxetine (n = 11), or placebo (n = 10) for 4 weeks. Fluoxetine 60 mg/day decreased mean daily alcoholic drinks from (X +/- SEM) 8.3 +/- 0.7 during baseline to 6.9 +/- 0.7 and decreased total drinks per 14 days from 115.8 +/- 9.3 to 96.5 +/- 9.5 (p less than 0.01; 17.3% decrease from baseline), with no significant increase in days of abstinence. Neither 40 mg/day fluoxetine nor placebo had effects on intake of alcohol. Fluoxetine 60 mg/day decreased total and mean daily alcoholic drinks compared with 40 mg/day fluoxetine (ANCOVA, both p less than 0.02), but neither dose of fluoxetine was different from placebo. Compared with placebo, both 40 mg/day fluoxetine and 60 mg/day fluoxetine no differences were detected between treatment groups, 60 mg/day fluoxetine increased mean daily nonalcoholic beverages from baseline (5.0 +/- 0.4 to 5.6 +/- 0.3, p less than 0.01) and increased daily cigarettes smoked (from 25.1 +/- 4.6 to 26.9 +/- 4.5, p less than 0.05), whereas no significant changes from baseline were observed with 40 mg/day fluoxetine or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Corticotropin-releasing factor is altered in brains of animals with high preference for ethanol.

Ethanol administered to rats has been shown to stimulate the hypothalamic-pituitary-adrenal axis. The present study describes alterations in brain CRF neuronal systems that accompanied the voluntary high consumption of ethanol by Wistar rats presented with a free choice between 6% ethanol and tap water. Hypothalamic CRF concentrations (outside median eminence) were significantly increased in animals with a high preference for ethanol whereas concentrations of CRF in neurointermediate pituitary and medulla-pons were significantly decreased. No changes of CRF levels were evident in median eminence, frontal cortex, midbrain, thalamus, or cerebellum. Brain CRF concentrations in two strains of mice with genetically determined differential alcohol preference were measured. In ethanol-naive mice, there were documented differences in CRF concentrations, with an increase in frontal cortex levels, and a decrease in medulla-pons levels in the ethanol-preferring strain (C57BL/6J) compared to the nonpreferring strain (C3H/CRGL/2). Thus, certain brain CRF neuronal systems are preferentially affected by high ethanol consumption, and pre-existing differences in these systems may even contribute to the development of a high preference for ethanol.

Alcohol Drinking↗
PubMed1989

Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers.

There are several problems with the drugs currently used to decrease alcohol consumption (i.e., alcohol-sensitizing drugs, such as disulfiram). Their efficacy is unproven, they are associated with toxicity, and there are several contraindications for use. New therapies are needed because alcohol-related problems affect almost 20% of the adult population. A new strategy was developed that involves attenuation of alcohol intake via serotonin uptake inhibitors. Since several experiments showed that serotonin uptake inhibitors consistently attenuated ethanol intake in rats, we tested their effects in humans. In four randomized, double-blind, placebo-controlled studies serotonin uptake inhibitors (zimelidine, citalopram, viqualine, and fluoxetine) decreased total number of drinks consumed by early stage problem drinkers by an average of 20-30%. However, marked interindividual variations in the pattern of response to serotonin uptake inhibitors have been observed, and we have been unable to identify subject traits or drug factors that predict pattern of response. Effects on ethanol intake are distinct from the antidepressant properties of these drugs, and they are most likely due to facilitation of satiety signals. Because of these promising and consistent results, further testing in a therapeutic context is under way. Serotonin uptake inhibitors suggest an innovative approach for moderating ethanol intake in problem drinkers.

Alcohol Drinking↗
PubMed1989

Kinetic and dynamic interactions of oral viqualine and ethanol in man.

We have studied the interaction of viqualine, a 5-hydroxytryptamine (5-HT) uptake inhibitor, with ethanol in 16 healthy men aged 20 to 34 years. The subjects were randomly assigned to receive ethanol dosed to maintain blood alcohol concentrations of 17-22 mmol.l-1 (n = 8) or orange juice (n = 8) on each of two test days one week apart and preceded, in random order, by 3 days of viqualine 75 mg bd or placebo. Ethanol had no effect on steady-state viqualine concentrations or the inhibition of 5-HT uptake. Viqualine did not affect acetaldehyde concentrations or cause an aversive alcohol-sensitizing reaction. The deleterious effects of ethanol on word recall, manual tracking, body sway, and self-ratings of intoxication, sedation, and performance were not modified by the presence of viqualine. Within each beverage group performances and self-ratings on viqualine and placebo days were not different. The first dose of viqualine was associated with transient nausea. Viqualine and ethanol do not interact kinetically or dynamically on the variables examined in this study.

Acetaldehyde↗
PubMed1989

Differential effects of viqualine on alcohol intake and other consummatory behaviors.

Viqualine, a serotonin releaser and uptake inhibitor, was studied for its effects on consummatory behaviors (intake of ethanol and nonalcoholic beverages, cigarette smoking, and changes in body weight) in 29 men who were early-stage problem drinkers between 21 to 55 years of age. Subjects were randomly assigned to receive a placebo and either 100 mg/day viqualine (n = 15) or 200 mg/day viqualine (n = 14) orally in a double-blind crossover study. Viqualine administration and ethanol intake were assessed by self-reports and by measurement of drug and ethanol concentrations in body fluids. Compared with placebo, 100 mg/day viqualine did not decrease ethanol intake. However, 200 mg/day viqualine significantly decreased the total number of drinks consumed in a 14-day period (F1,12 = 5.3; p less than 0.05). An increase in the number of abstinent days was significant only for those subjects who received the placebo first (F1,6 = 11.3, p less than 0.02). Subjects reported a decreased interest in and decreased desire for alcohol during viqualine treatment. Patterns of response varied, but 64% of the subjects decreased the number of alcoholic drinks consumed and/or increased the number of days of abstinence by at least 25% during treatment with 200 mg/day viqualine compared with placebo treatment. Neither dose of viqualine had an effect on cigarette smoking or on consumption of nonalcoholic beverages, but subjects showed significant decreases in body weight with both doses. These findings indicate that viqualine both attenuates ethanol intake and reduces body weight in human beings.

Adult↗
PubMed1989

Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar).

A shortened 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome has been developed. This scale offers an increase in efficiency while at the same time retaining clinical usefulness, validity and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal.

Alcohol Withdrawal Delirium↗
PubMed1988

Limitations in the measurement of urine ethanol in clinical trials to monitor ethanol consumption.

Self-report of daily alcohol consumption has been used as the dependent variable in clinical trials to assess the effects of two serotonin uptake inhibitory drugs, zimelidine and citalopram. The validity of the dairy data was established by correlating concentration of ethanol in daily urine samples with number of reported standard alcoholic drinks (r = 0.62 for the 934 subject-days in the zimelidine study; r = 0.54 for the 3,103 subject-days in the citalopram study, both p less than 0.0001). The effects of factors other than inaccurate reporting, such as the range of values for reported daily drinks and subjects' drinking patterns, on the correlation coefficients for all subject-days and for individual subjects in the citalopram study are discussed. Sampling 50% or fewer of the 84 days of the citalopram study for each subject is economically advantageous and did not significantly change the values of the correlation coefficients or the rank positions of subjects but did increase the 95% confidence intervals for the correlation coefficients, indicating less certainty about the actual correlation coefficients and, therefore, the accuracy of a subject's self-report. The ability of urine ethanol concentration to validate objectively diaries of alcohol consumption is limited by factors that must be considered but are likely to be out of the investigator's control.

Adult↗
PubMed1988

Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines.

The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (less than or equal to 30 mg/day) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized, crossover single case study. Objective confirmation of drug use or of abstinence was performed by obtaining plasma benzodiazepine concentrations. The findings provide further documentation that sensory disturbances of short- and long-term duration are among the most distinctive clinical features of the benzodiazepine withdrawal syndrome.

Adult↗