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Biomedical subjects

C A Naranjo

Publications and source records attributed to C A Naranjo.

At least 37 records · Page 2Linked to original sources
PubMed1998

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.

Adult↗
PubMed1997

Development and evaluation of a clinical psychopharmacology educational curriculum.

Clinical psychopharmacology training at the University of Toronto (Toronto, Ontario, Canada) was in need of improvement. The authors developed and evaluated a Clinical Psychopharmacology Educational Curriculum to complement the education provided to trainees and staff. The program consisted of journal clubs, case rounds, and didactic research tutorials and lectures. The program was attended by staff, fellows, psychiatry residents, graduate pharmacology students, medical students, and pharmacists. No course credit or continuing medical education credits were offered for participating in the program. The program ran for two academic years (September 1994-June 1996). Anonymous evaluation forms were collected after the sessions. These evaluated content, presentation style, and educational value, each on a scale from 1 (unsatisfactory) to 5 (excellent). Ratings for each component of the curriculum were close to excellent. The case rounds were rated slightly better for presentation style and educational value. Positive ratings suggest that similar efforts, particularly using case-based methods, should be developed in other teaching hospitals contingent on availability of qualified faculty and funding.

Curriculum↗
PubMed1997

Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo.

BACKGROUND: Paroxetine is a frequently used antidepressant and a potent inhibitor of the CYP2D6 isozyme in vitro (inhibition constant [Ki] = 0.15 micromol/L). Most classic antipsychotic agents such as perphenazine are metabolized by the CYP2D6 isozyme and are often coadministered with antidepressant agents. This study assessed the extent of changes in CYP2D6 isozyme activity in vivo after pretreatment with paroxetine and its consequences on perphenazine kinetics and central nervous system effects. METHODS: Eight extensive metabolizers for CYP2D6 were administered a single dose of perphenazine (0.11 mg/kg orally) or placebo following a randomized double-blind design. Perphenazine plasma concentrations and effects were assessed for a period of 8 hours. Subsequently, subjects were treated with a standard therapeutic dose of paroxetine (20 mg/day orally) for 10 days and test sessions with perphenazine and placebo were repeated. RESULTS: Paroxetine treatment resulted in a twofold to 21-fold decrease in CYP2D6 activity (p < 0.001). After pretreatment with paroxetine, perphenazine peak plasma concentrations increased twofold to 13-fold (p < 0.01). This was associated with a significant increase in central nervous system side effects of perphenazine, including oversedation, extrapyramidal symptoms, and impairment of psychomotor performance and memory (p < 0.05). CONCLUSION: Coadministration of perphenazine after pretreatment with a standard therapeutic dose of paroxetine increased the plasma concentration and central nervous system side effects of perphenazine, primarily as a result of inhibition of the CYP2D6 isozyme. In patients who are at steady state with paroxetine, a reduction of perphenazine dose may be required to prevent central nervous system side effects.

Adult↗
PubMed1997

Using fuzzy logic to predict response to citalopram in alcohol dependence.

INTRODUCTION: The prediction of patient response to new pharmacotherapies for alcohol dependence has usually not been successful with standard statistical techniques. We hypothesized that fuzzy logic, a qualitative computational approach, could predict response to 40 mg/day citalopram and 40 mg/day citalopram with a brief psychosocial intervention in alcohol-dependent patients. METHODS: Two data sets were formed with patients from our studies who received 40 mg/day citalopram alone (n = 34) or 40 mg/day citalopram and a brief psychosocial intervention (n = 28). The output variable, "response," was the percentage decrease in alcohol intake from baseline. Input variables included age, gender, baseline alcohol intake, and levels of anxiety, depression, alcohol dependence, and alcohol-related problems. RESULTS: A fuzzy rulebase was created from the data of 26 randomly chosen patients who received 40 mg/day citalopram and was used to predict the responses of the remaining eight patients. Eight rules related response with depression, anxiety, alcohol dependence, alcohol-related problems, age, and baseline alcohol intake. The average magnitude of the error in the predictions (RMSE) was 2.6 with a bias (ME) of 0.6. Predicted and actual response correlated (r = 0.99; p < 0.001). A fuzzy rulebase was created from the data of 28 randomly chosen patients who received 40 mg/day citalopram and a brief psychosocial intervention and was used to predict the responses of the remaining five patients. Six rules related response with age, anxiety, depression, alcohol dependence, and baseline alcohol intake with good predictive performance (RMSE = 6.4; ME = -1.5; r = 0.96; p < 0.01). CONCLUSIONS: This study indicates that fuzzy logic modeling can predict response to pharmacotherapies for alcohol dependence.

Alcoholism↗
PubMed1997

Fuzzy logic pharmacokinetic modeling: application to lithium concentration prediction.

INTRODUCTION: We hypothesized that fuzzy logic could be used for pharmacokinetic modeling. Our objectives were to develop and evaluate a model for predicting serum lithium concentrations with fuzzy logic. METHODS: Steady-state pharmacokinetic data had been previously collected in 10 elderly patients (age range, 67 to 80 years) with depression who were receiving lithium once daily. Each patient had serial serum lithium concentration determinations over one 24-hour period. The resulting 137 data sets initially consisted of five input variables (age, weight, serum creatinine, lithium dose, and time since last dose) and one output variable (serum lithium concentration; range, 0.2 to 1.24 mmol/L). RESULTS: A fuzzy rulebase was created with 87 randomly chosen data sets, and predictions of serum lithium concentration were made on the basis of the remaining 50 data sets. All of the input variables except age and weight were identified as contributing to the fuzzy logic model. The average magnitude of the error in the predictions was 0.13 mmol/L (root mean squared error) with a bias (mean of the prediction errors) of 0.03 mmol/L. CONCLUSIONS: This study indicates that the use of fuzzy logic for pharmacokinetic modeling of lithium for serum concentration predictions is feasible.

Aged↗
PubMed1997

Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence.

The potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, tricyclic antidepressants and benzodiazepines. Many psychotropic medications have an affinity for the cytochrome P450 (CYP) enzymes which promote elimination by transforming lipid soluble substances into more polar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro studies provide a screening method for evaluating drug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predicting these metabolic kinetic drug interactions, case reports and controlled experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evaluating the clinical significance of a potential interaction including: (a) the nature of each drugs' activity at an enzyme site (substrate, inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic routes); (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme activity of the individual, phenotyping/genotyping information; (i) the level of risk of the individual experiencing adverse effects (e.g. the elderly) and (j) from an epidemiological perspective, the probability of concurrent use. This paper systematically reviews both the in vitro and in vivo evidence for drug interactions between SSRIs and other CNS drugs. As potent inhibitors of CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma concentrations of antipsychotic medications metabolised through this enzyme, including perphenazine, haloperidol, thioridazine and risperidone in patients who are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, resulting in higher plasma concentrations. Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase the plasma concentrations of secondary and tertiary tricyclic antidepressants. Sertraline and citalopram are less likely to have this effect. Fluvoxamine can increase the plasma concentrations of tertiary TCAs. Fluvoxamine inhibits, via CYP3A. CYP2C19 and CYP1A2, the metabolism of several benzodiazepines, including alprazolam, bromazepam and diazepam. Fluoxetine increases the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildely to moderately at usual therapeutic doses. Therefore the potential for interactions is less; however, the in vivo evidence is minimal. Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines. The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carb

Anti-Anxiety Agents↗
PubMed1997

Pharmacotherapy of late life mood disorders.

The pharmacotherapy of elderly patients with affective illnesses presents clinicians with a number of challenges. Changes associated with normal aging, as well as concomitant medical illnesses and their treatment, can affect the pharmacokinetics and pharmacodynamics of psychotropic drugs. Furthermore, the relative paucity of controlled trials with elderly patients necessitates a reliance on studies done on younger populations, which may be inappropriate. This review attempts to highlight how knowledge of the effects of aging on pharmacokinetics and pharmacodynamics can help clinicians optimize therapy for their older patients with affective disorders.

Aged↗
PubMed1997

Long-acting injectable bromocriptine does not reduce relapse in alcoholics.

Dopamine is one of several neurotransmitters that may mediate alcohol intake and dependence. A randomized, double-blind, placebo-controlled international, multicentre study was conducted to assess the effects of a long-acting injectable preparation of bromocriptine, a dopamine agonist, (Parlodel-LAR) in reducing relapse in 366 moderately/severely dependent alcoholics (DSM-III-R), drinking approximately 200 g alcohol (14.5 standard drinks) per day. After detoxification they were randomized to receive six monthly injections of bromocriptine 25 mg (n = 120), bromocriptine 50 mg (n = 124), placebo (n = 122). Brief psychosocial treatment was allowed. At 6 months there were no significant differences between treatment groups in rates of relapse to any drinking or to drinking > or = 5 days per month and > or = 3 drinks per day. Pre-treatment alcohol intake did not determine response. Efficacy ratings by subjects and investigators and adverse events, reported by 51% of subjects, did not differ between treatments. The results of this large study, in which compliance was enhanced by Parlodel-LAR, do not indicate that bromocriptine is efficacious in the maintenance of abstinence or reduced drinking. Possible reasons for the discrepancy between these conclusions and those of some previous clinical trials, in which bromocriptine was reported to reduce symptoms of alcohol withdrawal and dependence, are discussed.

Adolescent↗
PubMed1996

Research strategies to assess pharmacotherapies for alcoholism.

1. The development and implementation of standardized basic and clinical research strategies is necessary for the discovery and testing of new and effective pharmacotherapies for alcohol dependence. While many animal studies have indicated the involvement of central serotonin, endogenous opioids and dopamine, their exact mechanisms of action have not been fully discerned. One problem is the use of various animal models, making it difficult to compare or replicate results from different laboratories. 2. Once a drug appears to decrease alcohol intake in animals, assessing its effects in humans can be even more challenging. 3. Most drugs were developed and may be even registered for another indication, so Phase I trials must be repeated in heavy alcohol users in case the drug has behavioural, pharmacokinetic or pharmacodynamic interactions with alcohol. 4. Phase II trials, assessing the effects of the drug on alcohol intake, are usually radically different from the animal models: most are long (> 6 months), use varied designs, and accept only abstinence as successful outcome. Moderately dependent alcoholics, who comprise the majority of patients, prefer a goal of nonhazardous drinking. 5. In Phase III multicentre trials, especially international ones, it is almost impossible to control for potentially confounding variables, such as patient characteristics and concomitant psychosocial treatment. 6. Also, research in pharmacotherapies for alcoholism is influenced by external factors such as sources of funding and other resources. Thus, this methodical progression from Phase I to Phase III clinical trials is often abbreviated. 7. The authors developed a brief early Phase II clinical paradigm to assess pharmacotherapies for moderately dependent alcoholics, and conducted 3 studies with the serotonin uptake inhibitors, citalopram and fluoxetine, and a serotonin antagonist, ritanserin. This paradigm, which includes a short (1 to 2 weeks) outpatient phase and two experimental drinking sessions, measures alcohol intake, desire to drink, alcohol's subjective effects, and intoxication. While it may have limited relevance to a goal of abstinence, it is efficient and economical to screen drug effects on alcohol intake and suggest mechanisms (desire to drink, subjective effects). It is also the only human model concordant with results in animals. 8. Development of new pharmacotherapies for alcoholism may benefit from acceptance of both abstinence and moderation of drinking as acceptable treatment goals.

Alcohol Deterrents↗
PubMed1996

Pharmacokinetic changes in the elderly. Do they contribute to drug abuse and dependence?

The elderly frequently use psychoactive drugs including alcohol (ethanol), benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence. Theoretically, the changes in pharmacokinetics of these agents in the elderly may modify their abuse and dependence potential. In the elderly, blood alcohol concentrations following an oral dose are higher, alcohol withdrawal syndrome follows a more severe and protracted clinical course and requires treatment with higher doses of chlordiazepoxide than needed for younger adults. However, there is no direct evidence that supports an increased direct abuse and dependence potential of alcohol because of its altered kinetics in the elderly. In the case of oxidatively metabolised benzodiazepine, both age-related pharmacokinetics and pharmacodynamic changes may increase their clinical effects in the elderly. The hypothesis that benzodiazepines have an increased abuse and dependence potential in the elderly has not been tested. Many of the benzodiazepines (e.g. alprazolam, triazolam and midazolam) are metabolised by the cytochrome P450 (CYP)3A subfamily. The pharmacokinetics of these agents may be modified by inhibition of CYP3A due to concurrently administered medications such as selective serotonin reuptake inhibitors. Unfortunately, data on the direct measures of abuse and dependence potential of benzodiazepines are not available in the elderly. Thus, a conclusive statement on the contribution of age-related pharmacokinetic changes to benzodiazepine abuse and dependence cannot be made at the present time. The clinical effects of codeine do not appear to change with age. Codeine is O-demethylated to its active metabolite morphine by the genetically polymorphic CYP2D6 isozyme. The activity of this isozyme is unaltered by age, gender or smoking habits; however, it is subject to potent inhibition by some of the frequently used medications in the elderly, such as the antidepressants paroxetine and fluoxetine. This may result in an impairment in O-demethylation of codeine to morphine and may lead to a decrease in the abuse and dependence potential of codeine. Conversely, those with a very rapid CYP2D6 catalytic activity may have an increased potential for codeine abuse and dependence. The clinical significance of age-related pharmacokinetic changes should be evaluated within the context of clinical practice. Most physicians are inclined to prescribe lower doses to the elderly, which may offset the potential impact of altered pharmacokinetics on the abuse and dependence potential of psychoactive agents. In summary, the available data are not sufficient for a definitive conclusion on whether the pharmacokinetic changes in the elderly translate to an increase in the abuse and dependence potential of alcohol, benzodiazepines or opioids. In particular, the data on age-associated changes in direct measures of abuse potential of these agents are missing. Future comparative systemic pharmacokinetic-pharmacodynamic studies assessing pertinent outcome measures on abuse and dependence potential of commonly used psychoactive drugs are required to resolve the ongoing controversy on risk factors for drug abuse and dependence in the elderly.

Aged↗
PubMed1995

Comparison of the Bayesian approach and a simple algorithm for assessment of adverse drug events.

The differential diagnosis of severe adverse drug events can be based on clinical judgment, algorithms, or the Bayesian approach. The Bayesian Adverse Reactions Diagnostic Instrument (BARDI) calculates the posterior probability (PsP) in favor of a specific drug cause based on background (e.g., epidemiologic) and case information (e.g., time of onset). Although BARDI discriminates between drug- and nondrug-induced adverse events, its apparent complexity may limit its use. BARDI results were compared with those from an algorithm for rating the probability that an adverse drug event is drug-induced (Adverse Drug Reaction Probability Scale, or APS) that is still commonly used. APS scores were obtained by two independent raters for 106 challenging cases that had been analyzed from 1 to 5 years ago with BARDI (91 cases of hypersensitivity, 12 cases of hematologic toxicity, and three cases of pulmonary toxicity); 130 ratings were generated because of the use of multiple drugs. APS scores for the two raters were highly correlated (r = 0.79; p < 0.0001). Probabilities of drug causation with use of BARDI versus average APS scores were significantly correlated (rs = 0.45; p < 0.0001). However, BARDI better distinguished cases that were highly probable (n = 83; PsP > or = 0.75) or highly improbable (n = 30; PsP < or = 0.25), whereas the APS rated the majority of these cases in the midrange (n = 128; range of APS, 1 to 8.9). These results suggest that APS and BARDI evaluations are concordant. Thus the APS may be an effective screening tool, although BARDI can better discriminate drug from nondrug-induced cases and may be more appropriate for serious cases of adverse drug reactions.

Algorithms↗
PubMed1995

Effects of citalopram and a brief psycho-social intervention on alcohol intake, dependence and problems.

Citalopram (C) decreased alcohol intake and desire to drink in short-term (2-4 weeks) studies with no other treatment. We tested the long-term effects of C combined with a brief psycho-social intervention. After a 2-week baseline, mildly/moderately dependent alcoholics (35 males, 27 females) were randomized, double-blind to 12 weeks of C 40 mg/day (n = 31) or placebo (P) (n = 31) and a brief psycho-social intervention with follow-ups at 4 and 8 weeks post-treatment. Alcohol intake was monitored daily and alcohol dependence (ADS) and problems (MAST) were assessed at intake and post-treatment. During the first week, the decrease (%) from baseline daily alcoholic drinks (mean +/- SEM) was greater with C (47.9 +/- 5.1 from 6.5 +/- 0.6) than with P (26.1 +/- 4.2 from 5.8 +/- 0.4) (p < 0.01). However, the 12-week decreases with C (35.1%) and P (38.8%) were similar. There were gender differences within the C group. The males had higher MAST scores at intake (mean +/0 SEM = 10.4 +/- 0.8; n = 15) than the females (6.4 +/- 0.9, n = 16) (p < 0.01) and were slightly heavier drinkers during baseline (7.1 +/- 0.9 vs. 5.9 +/- 0.9 drinks/day, NS). The response to C was greater in males (44% decrease) than females (26%) (p < 0.05) and correlated with MAST scores (r = 0.44, p = 0.01), but not with baseline alcohol intake (r = 0.2, NS). Craving and liking for alcohol and alcohol dependence (ADS) and problems (MAST) decreased similarly with C and P (p < 0.01). Thus, the short-term effects of C were replicated but no long-term effect was detected. Tolerance to citalopram, perhaps through some adaptive neurobiological changes, may have developed. The potential therapeutic use of C as a useful pharmacological adjunct in alcoholics remains to be determined.

Adult↗
PubMed1995

Ritanserin, a central 5-HT2 antagonist, in heavy social drinkers: desire to drink, alcohol intake and related effects.

Ritanserin, a 5-HT2 receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19-63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 mg/day (n = 12), ritanserin 10 mg/day (n = 13) or placebo (n = 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS1) and treatment (EDS2); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS2, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS1 desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 mg/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.

Adult↗
PubMed1995

Recent advances in geriatric psychopharmacology.

Psychopharmacotherapy of the elderly must take into account the effects of age-related changes in the structure and function of the brain and various organs. In general, older people are more sensitive than young people to both the therapeutic and toxic effects of psychotropic medications, necessitating lower doses and longer dosage intervals. This holds true for the treatment of 5 major types of psychiatric illness (depression, bipolar disorder, anxiety, psychotic disorders and dementia). The tricyclic antidepressants, although efficacious, inexpensive, and backed by 30 years of experience, are less well tolerated by the elderly than are newer antidepressants such as the selective serotonin uptake inhibitors. Problems with monoamine oxidase (MAO) inhibitors, including orthostatic hypotension and restrictions in diet and other medication use, have been overcome by the advent of reversible selective inhibitors of MAO-A, but the efficacy of these in the elderly has yet to be proven in clinical trials. Lithium remains the mainstay for the treatment of bipolar disorder. However, careful dosing and monitoring of plasma lithium concentrations are required in the elderly due to changes in pharmacokinetics and pharmacodynamics which make older patients very sensitive to the toxic effects of this medication. Similarly, age-related changes in the pharmacokinetics and pharmacodynamics of the benzodiazepines, the most frequently prescribed medications for anxiety in the elderly, result in recommendations for lower doses and preferential use of those agents metabolised by conjugation (e.g. oxazepam). Buspirone, a partial serotonin 5-HT1A-agonist which is better tolerated than benzodiazepines in the elderly, may be used as an alternative. The elderly are extremely sensitive to extrapyramidal adverse effects which the typical antipsychotics (neuroleptics) exhibit to varying extents. The selection of a suitable agent for the treatment of a psychotic disorder should be based upon the adverse effect profile of the drug and the specific symptoms and situation of the patient. The newer atypical antipsychotics, clozapine and risperidone, have yet to be well-studied in the elderly. Dementia, exemplified by Alzheimer's disease, is almost exclusively an illness of the elderly. Only one medication, tacrine, has been approved for its treatment, based on extensive basic research and positive results of several clinical trials. Its long-term benefits have yet to be determined and it has several adverse effects, including a tendency to increase liver enzymes to the extent that the medication has to be discontinued.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1995

Low endogenous dopamine function in brain predisposes to high alcohol preference and consumption: reversal by increasing synaptic dopamine.

Using inbred strains of mice that differ widely in their innate preference for and consumption of ethanol, we demonstrate, in ethanol-preferring C57BL/6J (C57) mice, decreased dopamine (DA) content and turnover in the terminals of the mesolimbic and mesostriatal dopamine neurons, compared with ethanol-avoiding DBA/2J and BALBc mice. These data suggest that genetically determined hypodopaminergic function in these pathways plays a role in the predisposition to high voluntary intake of ethanol. DA turnover in these areas was selectively increased by ethanol in C57 mice, which suggests that these DA neurons are among the central substrates of ethanol action in brain. In keeping with this hypothesis, augmenting synaptic DA concentrations by enhancing the synthesis by L-3-4-dihydroxyphenylalanine with carbidopa, or by decreasing its degradation by monoamine oxidase-B blockade with selegiline, led to marked decreases in ethanol preference and in the high voluntary consumption of ethanol in C57 mice. The selegiline-mediated decrease in ethanol preference and drinking in C57 mice could be blocked selectively by D1 and D2 DA receptor antagonists, which suggests that DA activity at D1 and D2 receptors plays an important role in this behavior. Indeed, the high preference for ethanol in C57 animals could be attenuated by direct DA receptor activation by either D1 or D2 agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

Computer-assisted evaluation of adverse events using a Bayesian approach.

The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is complex because for each adverse event there are many possible drug and nondrug causes. Recently efforts have been made to computerize causality assessment methods. A new computerized, user-friendly diagnostic aid for Bayesian assessment of adverse drug events (MacBARDI-Q&A) is described. This computer program performs a differential diagnosis on cutaneous reactions suspected of being drug-induced. The authors' results indicate that development of a valid, simple and user-friendly computerized procedure for evaluating adverse drug events is possible. The ongoing development and application of MacBARDI-Q&A and other similar programs should improve the evaluation of putative adverse drug reactions.

Anticonvulsants↗
PubMed1994

Improving the diagnosis of hypersensitivity reactions associated with sulfonamides.

The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is difficult because symptoms are seldom pathognomonic. The authors compared the performance of two new diagnostic aids in the differential diagnosis of 27 cases of skin reactions associated with sulfonamide therapy. One test, the Bayesian Adverse Reaction Diagnostic Instrument (BARDI), calculates the posterior probability (PsP) of a drug being the etiology of an idiosyncratic ADR. The other, the lymphocyte toxicity assay (LTA), is a biochemical test that determines the percent of cell death because of toxic metabolites of a drug. Cases were assessed independently and blindly by BARDI and then the LTA. Skin reactions consisted of 19 exanthematous eruptions, 2 vasculitis, 1 erythema multiforme, and 5 urticarial rashes. BARDI indicated that the drug was very likely associated with 20 adverse events (PsP = 0.59 to 0.99); and unlikely to have caused 7 (PsP = 0.02 to 0.38). The LTA showed that 19 patients (70%) were test positive, and 8 were test negative. Comparing BARDI to LTA showed that BARDI had 79% sensitivity and 67% accuracy, but only 38% specificity. However, when the results of the LTA were incorporated into the calculation of the PsP based on this comparison, BARDI indicated that the drug was very likely associated with 18 reactions (PsP = 0.61 to 0.99) and unlikely to have caused 9 reactions (PsP = 0.003 to 0.47). The agreement increased from 67% to 96%. These findings indicate that the accuracy of diagnosis of idiosyncratic ADRs improved when the results of BARDI and LTA were combined. These findings also crossvalidate the results obtained by using BARDI.

Adolescent↗