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Biomedical subjects

U E Busto

Publications and source records attributed to U E Busto.

28 records · Page 2Linked to original sources
PubMed1997

The efficacy, safety and tolerability of antidepressants in late life depression: a meta-analysis.

BACKGROUND: To determine the efficacy, safety and tolerability of antidepressants in depressed elderly patients. METHODS: Search for randomized controlled double-blind studies evaluating atypical antidepressants (ATYPs), reversible inhibitors of monoamine oxidase-A, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants in moderate/severe depressed patients > or = 60 years for > or = four weeks. The random effects model (single-arm; comparative) was used to aggregate efficacy, safety and dropout. RESULTS: No difference in single-arm aggregation of outcomes for four antidepressant classes. Comparative analyses showed no statistical difference between outcomes, except SSRIs had a higher response rate than ATYPs. CONCLUSION: Elderly show no differences in antidepressant class outcomes. LIMITATIONS: Heterogeneity and lack of power. CLINICAL RELEVANCE: There is little advantage for antidepressant classes over another in the aged.

Age Factors↗
PubMed1997

Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.

Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P450 2D6, which is inactive in about 7% of Caucasians [poor metabolizers (PMs)] and can be inhibited by quinidine pretreatment in the remainder [extensive metabolizers (EMs)]. If hydromorphone, having a substantially higher mu-receptor affinity than hydrocodone, contributes importantly to the physiological and subjective effects of oral hydrocodone, then PMs should be less responsive to the same doses, and quinidine pretreatment should cause EMs to temporarily respond as PMs. Seventeen EMs and 8 PMs who previously responded positively to hydromorphone s.c. received placebo and hydrocodone (10 mg, 15 mg and 22.5 mg p.o.) and were retested with their favorite dose after placebo or quinidine (100 mg) pretreatment; physiological and subjective measures were collected at base line and four times after drug administration, and urine was collected for 8 hr. EMs and PMs were equally responsive to oral hydrocodone, and quinidine had no consistent effect on their responses, even though quinidine abolished the pre-existing metabolic differences in hydromorphone production, as measured in urine. These data suggest only a small role of hydromorphone in eliciting abuse-related responses to oral hydrocodone.

Cytochrome P-450 CYP2D6 Inhibitors↗
PubMed1996

Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence.

This study aimed to evaluate the concurrent and lifetime psychiatric comorbidity and drug use patterns in patients admitted to the hospital for detoxification from benzodiazepines. Psychiatric assessments using the Structured Clinical Interview for DSM-III-R with a psychosis screening module (SCID-P and II) were conducted in 30 inpatients admitted to the medical unit treatment unit of the Clinical Research and Treatment Institute of the Addiction Research Foundation for the treatment of severe benzodiazepine dependence. Patients (mean age, 36 years; range, 22-58; number of DSM-III-R criteria met for benzodiazepine substance dependence, > or = 7 out of 9 [73%], all 9 criteria [40%]) used benzodiazepines and other drugs over prolonged periods of time at high doses, and their daily functioning was substantially impaired (Mean Global Assessment of Functioning Score, 48; range, 31-60). The most common lifetime psychiatric diagnoses were major depression (33%), other psychoactive drug dependence (100%) (opioids, 77%; alcohol, 53%), and panic disorder (30%). Current psychiatric diagnoses in addition to benzodiazepine dependence included other psychoactive substance use disorders (83%) (opioids, 67%; cocaine, 13%; multiple concurrent substance use, 17%), panic disorder (13%), and generalized anxiety disorder, (20%). Personality disorders included antisocial (42%), avoidant (25%), and borderline (17%). These findings demonstrate that in patients severely dependent on benzodiazepines, additional psychoactive substance use and mental disorders are prominent. The pattern of drug use and psychiatric comorbidity differentiates these patients from therapeutic-dose benzodiazepine users.

Adult↗
PubMed1996

Benzodiazepine use in Chile: impact of availability on use, abuse, and dependence.

This study tested the hypothesis whether over-the-counter benzodiazepine availability influenced patterns of benzodiazepine use, abuse, and dependence in Chile. If over-the-counter availability represents a major risk factor leading to benzodiazepine substance use disorders, rates of abuse, and dependence would be significantly higher among over-the-counter benzodiazepine users than among prescription drug users. The study was a household survey of a stratified sample (N = 1,500) of the Santiago (Chile) population performed by trained interviewers. Data were collected by structured questionnaires on demographic characteristics, drug use, psychoactive substance use disorders, and other psychosocial variables. Past-year prevalence of benzodiazepine use was 31.4%, daily use of benzodiazepines for > or = 12 months, 5.9%, and subjects who met DSM-III-R criteria for dependence, 3.3%. Seventy-four percent of subjects obtained the benzodiazepine over-the-counter (always 45%; sometimes 29%). No subject acknowledged recreational benzodiazepine use or met criteria for benzodiazepine abuse. Use, long-term use, and dependence occurred equally frequently among both over-the-counter and prescription benzodiazepine users. Results suggest that although over-the-counter availability increases benzodiazepine use, it is not a major risk factor that leads to benzodiazepine abuse and/or dependence.

Adolescent↗
PubMed1993

CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone.

The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6-B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O-demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O-demethylation in the three groups were 28.1 +/- 10.3, 3.4 +/- 2.4, and 5.0 +/- 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more "good opiate effects" and fewer "bad opiate effects" than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.

Cytochrome P-450 CYP2D6↗
PubMed1991

Drug metabolism and interactions in abuse liability assessment.

The interpretation of acute abuse liability studies and drug interaction studies would be importantly strengthened by the routine inclusion of drug concentration measurements at appropriate sampling times. Reliance on mean kinetic data misrepresents the variation in drug kinetics and fails to take experimental advantage of the natural differences in the population which may represent the extremes of abuse risk. Pharmacokinetic-pharmacodynamic studies to better understand the relationship of plasma drug concentration, drug concentration in the receptor biophase and specific drug reinforced behaviour will ensure proper study design and yield useful theoretic information. Multi- and poly-drug abuse (including heavy smoking and heavy ethanol use) are very common. Such patterns of use can have quite large effects on drug kinetics. Because of the potentially large qualitative and quantitative differences in drug metabolism and kinetics between pre-clinical species and the human, data should be gathered at the earliest possible time with respect to human metabolic rates, patterns, and identification of inhibitors. The availability of human liver microsomes facilitates such studies.

Dose-Response Relationship, Drug↗
PubMed1991

Anxiolytics and sedative/hypnotics dependence.

Anxiolytics and sedative/hypnotics are commonly used drugs. Benzodiazepines have largely replaced barbiturate and non-barbiturate anxiolytics and sedative/hypnotics as they are as effective and safer. Experiments in laboratory animals have shown that chronic administration of benzodiazepines tested to date can induce physical dependence. The severity of the withdrawal syndrome is clearly related to the dose, duration of administration and elimination rate of the drugs. It is now also clear that high doses of barbiturates and benzodiazepines can induce physical dependence in humans. In addition, a withdrawal syndrome after discontinuation of chronic benzodiazepine therapeutic treatment, with and without tolerance, has been well characterized. Symptoms may resemble those of anxiety or 'rebound' phenomena but some are typical of withdrawal. A relationship between benzodiazepine discontinuation and self-administration has been well documented. Negative reinforcement associated with a reduction of withdrawal symptoms may play a role supporting persistent benzodiazepine use.

Anti-Anxiety Agents↗
PubMed1991

Long-term alprazolam use: abuse, dependence or treatment?

Concern about persistent benzodiazepine use should be informed by data about reasons for such use. Consecutive long term alprazolam users (n = 25) admitted to an advertised outpatient program for discontinuation were characterized with respect to alprazolam use patterns and lifetime and current Axis I and II disorders. Patient characteristics were: females 50 percent; mean age, 46 +/- 12 yrs; prior medication use--benzodiazepines, 47 percent, antidepressants, 23 percent; median duration of use 104 +/- 96 wks; median daily dose, 0.5 mg; continued effectiveness of alprazolam 50 percent. Over the duration of use patients shifted their initial pattern of use from as prescribed to a self-controlled "as required" basis (p less than .05). Interviews using the Structured Clinical Interview for DSM-III-R (SCID) yielded diagnoses of DSM-III-R alprazolam dependence in all patients plus at least one additional psychiatric diagnosis in 65 percent (Axis I 65%; Axis II 39%). Most persistent alprazolam use does not represent abuse or addiction as usually understood. These data are most consistent with the interpretation that alprazolam is the most recent benzodiazepine used by patients to help control clinically important psychopathology and that most users make efforts to control or stop use.

Adult↗
PubMed1989

A clinical scale to assess benzodiazepine withdrawal.

The objective, sensitive, and reliable quantitation of withdrawal symptoms is essential to assess physical dependence on drugs. Data collected from 23 patients abusing high doses of benzodiazepines (mean diazepam dose equivalents, 150 mg/day; range, 40-500) and from 40 long-term therapeutic users randomized to receive either placebo (N = 19) or diazepam (N = 21; mean diazepam dose equivalents, 15 mg/day; range, 5-40; mean duration of use, 72 months; range, 6-240) were analyzed. Information on the type and severity of symptoms was obtained from several assessment instruments. In the high-dose abuse group, plasma benzodiazepine concentrations were measured daily and the 3 consecutive days of greatest relative daily fall were considered the critical withdrawal period. Selection of the 22 items of the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) was based on statistically significant differences between baseline and critical withdrawal periods in high-dose subjects and between symptoms associated with placebo and diazepam in low-dose subjects, using contingency tables and logistic regression analysis. Of the 104 symptoms measured by the assessment instruments, 22 symptoms were found to distinguish withdrawal from prewithdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗