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C A Naranjo

Publications and source records attributed to C A Naranjo.

At least 55 records · Page 3Linked to original sources
PubMed1994

Serotonin-altering medications and desire, consumption and effects of alcohol-treatment implications.

The relationship between serotonin neurotransmission and alcohol consumption (AC) was first determined in preclinical studies. AC generally increases following treatments which decrease serotonin activity, and levels of 5-HT and metabolites are low in some brain regions of alcohol-preferring rats. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled trials, SUI consistently decreased short-term (2-4 weeks) AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Some subjects decreased AC by up to 60%. The effects of SUI on AC were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI decreased desire to drink and liking for alcohol, suggesting a mechanism of action, to be considered in the development of treatments to reduce AC and prevent relapse. However, while an adjunctive brief psychosocial intervention enhanced the short-term effect of a SUI, the long-term (12-week) effects of SUI and placebo were similar. Other drugs acting on the 5-HT system have been tested in humans, but results are inconclusive. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). Ritanserin, a 5-HT2 antagonist, reduced desire to drink and prevented relapse in a small (n = 5) study, and there was some indication that it reduced desire to drink and enhanced alcohol effects without reducing AC, in another study. The therapeutic potential of these medications is being studied. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for AC.

Alcohol Drinking↗
PubMed1994

Enhanced differential diagnosis of anticonvulsant hypersensitivity reactions by an integrated Bayesian and biochemical approach.

OBJECTIVE: The differential diagnosis of hypersensitivity reactions associated with anticonvulsants requires accuracy because of the many implications for patient management. We tested an integrated Bayesian and biochemical diagnostic approach. METHODS: The patients were analyzed clinically by two tests. One test, the Bayesian Adverse Reaction Diagnostic Instrument (BARDI), calculates the posterior probability of a drug being the cause based on epidemiologic and case data. The other, the lymphocyte toxicity assay, is an in vitro rechallenge that determines the percentage of cell death attributable to a drug's toxic metabolites. The setting for the study was an adverse drug reaction clinic at Sunnybrook Health Science Centre and the Hospital for Sick Children, Toronto, Ontario, Canada. Fifty-one patients who had hypersensitivity reactions after receiving aromatic anticonvulsants were tested. Four of these patients had more than one reaction reported, with different anticonvulsants generating 56 distinct events. RESULTS: Compared to the lymphocyte toxicity assay, BARDI had 94% sensitivity, 93% accuracy, and 50% specificity. When lymphocyte toxicity assay data were incorporated into BARDI, agreement rose from 93% to 100%. BARDI also identified which drug was a more likely cause for 11 patients receiving multiple anticonvulsants. CONCLUSION: These findings show that BARDI and the lymphocyte toxicity assay have high concordance and, when used in an integrated approach, these tests can improve the diagnostic accuracy and enhance the management of patients with hypersensitivity reactions.

Adolescent↗
PubMed1994

Fluoxetine attenuates alcohol intake and desire to drink.

Several serotonin uptake inhibitors, including the long-acting fluoxetine, have been found to decrease alcohol intake in moderately dependent alcoholics. While the mechanism of their effect is not fully elucidated, a previous study with citalopram indicated that decreased desire to drink may be an important factor. Therefore, we tested fluoxetine effects on alcohol intake and desire to drink in a placebo-controlled study. Subjects, recruited by advertisement, were mildly/moderately dependent alcoholics (12 male, four female, aged 19-59 years, healthy, non-depressed) who did not believe they had a drinking problem and were not requesting treatment. After a 1 week baseline they received, single-blind, 2 weeks placebo followed by 2 weeks fluoxetine 60 mg/day. As out-patients, subjects recorded daily standard drinks (13.6 g ethanol) and rated interest, desire, craving and liking for alcohol biweekly. Each out-patient period was immediately followed by a double-blind experimental drinking session. Out-patient daily drinks slightly decreased during fluoxetine to 6.6 +/- 0.9 (mean +/- S.E.M.) compared with during placebo (7.16 +/- 0.95, p = 0.07, N.S.) and baseline (7.18 +/- 1.0, p > 0.1, N.S.). Desire, interest and craving for alcohol decreased during fluoxetine vs placebo baseline (p < 0.05), but not vs placebo. Appetite loss and decrease in food intake (p < 0.01, fluoxetine vs placebo) correlated with each other (r = 0.91, p < 0.01) but neither correlated with decrease in alcohol intake (appetite: r = 0.26, N.S.; food intake: r = 0.22, N.S.). Weight loss occurred during fluoxetine (p < 0.05 vs placebo) but did not correlate with decrease in alcohol intake (r = 0.1, N.S.). In the experimental drinking sessions after placebo and fluoxetine treatments subjects rated their desire for each of 18 mini-drinks (each one-third of a standard drink) offered at 5 min intervals. Fluoxetine decreased desire to drink throughout the sessions; both mean and maximum desire ratings were lower after fluoxetine than after placebo (ANOVA, p < 0.05). Therefore, fluoxetine seems to have a robust effect on decreasing desire for alcohol. We propose that in the absence of intention by subjects to reduce drinking, their habitual drinking patterns mitigated against reduced consumption in the out-patient phase. However, fluoxetine could be a useful adjunct for patients in a treatment context who are motivated to reduce their drinking.

Adult↗
PubMed1994

Treatment of alcohol withdrawal syndrome.

Treatment of the alcohol withdrawal syndrome is the first step towards the rehabilitation of alcohol-dependent patients. The objectives of treatment are relief of symptoms, prevention of complications and a smooth transition into a long-term rehabilitation programme. Recently, progress has been made in the clinical management of the alcohol withdrawal syndrome through standardization of the assessment using the CIWA-A scale and frequent monitoring of clinical findings, recognition of the efficacy of non-pharmacological interventions (i.e. standardized supportive care) and simplification of pharmacotherapy by optimizing the use of long-acting benzodiadepines via a loading dose technique. Benzodiazepines, because of their cross-tolerance with ethanol, wide margin of safety and low potential for physical dependence and tolerance, are very effective and are the drugs of choice for the treatment of the alcohol withdrawal syndrome.

Adrenergic beta-Antagonists↗
PubMed1993

Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption.

Variations in serotonin neurotransmission influence alcohol consumption (AC). Levels of 5-HT and metabolites are low in some brain regions of alcohol preferring rats and in CSF of alcoholics. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled clinical trials, SUI have consistently decreased AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Effects were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI also decreased desire to drink and liking for alcohol, thus suggesting a mechanism for effects. Other drugs acting on the 5-HT system have been tested in humans, but results are difficult to interpret. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased alcohol craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). The therapeutic potentials of these medications are being studied. For example, SUI effects on AC were enhanced by a brief psychosocial intervention. Since SUI decrease urge to drink, they may be suitable pharmacological adjuncts in relapse prevention strategies. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for reducing AC.

Alcohol Drinking↗
PubMed1993

Behavioural correlates of alcohol intoxication.

Alcohol is used in most cultures despite knowledge of the physical, psychological and social problems associated with its abuse. Behavioural impairment is a function of several factors, including blood alcohol concentration (BAC) and the rate of alcohol metabolism by alcohol dehydrogenase and the microsomal ethanol-oxidizing system. Their availability and activity depend upon alcohol use history, ethnicity, other drug use and gender. Adverse social consequences related to alcohol intoxication include impaired driving, acts of aggression and violence towards self and others, and various types of accidents. About 40% of all fatal traffic accidents in Canada and the US in 1986-1987 were alcohol-related. Similar statistics have been reported in the UK and Europe (e.g. Sweden). The risk of a fatal car accident increases exponentially with a driver's BAC, prompting recommendations to lower the legal BAC limit for driving and piloting aircraft. Risks of falls, drownings, and fires and burns may also be increased by alcohol intoxication. At least 22% of work-related accidents may have involved alcohol use. These data are probably conservative estimates as under-reporting of alcohol use is likely. Alcohol facilitates aggressive behaviours, but it is difficult to separate the pharmacological effect from psychosocial effects or some other common factor (e.g. low CSF levels of the serotonin metabolite 5-H1AA have been reported in alcoholics, suicide attempters, violent offenders). In addition, alcohol interacts with other drugs to increase or decrease their behavioural and therapeutic effects. An acutely high BAC inhibits the metabolism of other CNS depressants (e.g. benzodiazepines), but long-term alcohol use increases the metabolism of most drugs. A potential amethystic agent, to block or reverse alcohol's effects, has been identified in preclinical studies (Ro15-4513, an imidazobenzodiazepine). Some clinical studies indicated that naloxone, lithium, ibuprofen, zimeldine and catecholamine agonists may reduce ethanol-induced behavioural or cognitive effects but the results have not been consistently replicated. More research is needed to determine the potential clinical use of amethystic agents and other pharmacotherapies in the prevention and treatment of problem behaviours associated with alcohol abuse and intoxication.

Accidents↗
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↗