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U Busto

Publications and source records attributed to U Busto.

At least 19 recordsLinked to original sources
PubMed2001

Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4.

We have identified CYP2C19 and CYP3A4 as the principal cytochrome P450s involved in the metabolism of flunitrazepam to its major metabolites desmethylflunitrazepam and 3-hydroxyflunitrazepam. Human CYP2C19 and CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 and 108 microM, respectively, and 3-hydroxyflunitrazepam with Km values of 642 and 34.0 microM, respectively. In human liver microsomes (n = 4) formation of both metabolites followed biphasic kinetics. Desmethylflunitrazepam formation was inhibited 31% by S-mephenytoin and 78% by ketoconazole, suggesting involvement of both CYP2C19 and CYP3A4. Formation of 3-hydroxyflunitrazepam was also significantly inhibited by ketoconazole (94%) and S-mephenytoin (18%). In support of these chemical inhibition data, antibodies directed against CYP2C19 and CYP3A4 selectively inhibited formation of desmethylflunitrazepam by 26 and 45%, respectively, while anti-CYP3A4 antibodies reduced 3-hydroxyflunitrazepam formation by 80%. Our data also suggest that CYP1A2, -2B6, -2C8, -2C9, -2D6, and -2E1 are not involved in either of these metabolic pathways. We estimate that the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 and 37%, respectively, at therapeutic flunitrazepam concentrations (0.03 microM). We conclude that the polymorphic enzyme CYP2C19 importantly mediates flunitrazepam demethylation, which may alter the efficacy and safety of the drug, while CYP3A4 catalyzes the formation of 3-hydroxyflunitrazepam.

Anti-Anxiety Agents↗
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

Comparative abuse liability of sertraline, alprazolam, and dextroamphetamine in humans.

Sertraline is an effective antidepressant acting as a selective serotonin reuptake inhibitor. The subjective and behavioral effects of sertraline were studied and compared with the effects of alprazolam and dextroamphetamine in a within-subject, randomized, double-blind study in 20 volunteers aged 18 to 46 years. These subjects were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish secobarbital, 150 mg, from placebo and to report positive subjective effects of secobarbital in an experimental setting. The following drug conditions were tested: sertraline, 100 and 200 mg; alprazolam, 1 mg; dextroamphetamine, 10 mg; and placebo. Drug effects were assessed with an objective test of psychomotor performance, subject-rated questionnaires, and observer-rated scales. Both alprazolam and dextroamphetamine were distinguishable from placebo on most measures, but sertraline produced effects discernable from placebo on only a few measures. At 1 hour postdrug administration, dextroamphetamine and alprazolam produced positive effects on several measures of elation, euphoria, and drug liking greater than placebo and both doses of sertraline. In contrast, sertraline produced higher scores on measures of dysphoria and physical unpleasantness than did the other drug conditions. Observer ratings of satisfaction with the drug and other pharmacologic effects were consistent with these findings. Results from this study indicate that sertraline, at the doses tested, does not possess the behavioral effects profile considered to be indicative of abuse potential when compared with alprazolam and dextroamphetamine.

1-Naphthylamine↗
PubMed1995

Clinical aspects of chronic use of alprazolam and lorazepam.

OBJECTIVE: The authors' goal was to determine the clinical characteristics of persistent users of alprazolam or lorazepam who wished to discontinue their medication. METHOD: Long-term users (daily use for more than 3 months) of alprazolam (N = 34) or lorazepam (N = 97) who entered an outpatient treatment program for discontinuation of benzodiazepines were carefully assessed. Detailed histories of benzodiazepine use were obtained; a structured interview was used to make psychiatric diagnoses based on DSM-III-R criteria. RESULTS: The majority of patients were using low therapeutic doses of medication (lorazepam: mean = 2.7 mg/day; alprazolam: mean = 1.2 mg/day) and had either maintained their initial daily dose over time or decreased it. Individuals tended to shift their use of medication from an as-prescribed to an as-needed pattern. Forty-seven percent of the patients were diagnosed with at least one current anxiety disorder, most commonly generalized anxiety. At least one diagnosable personality disorder was found in 45% of the patients, most commonly obsessive-compulsive personality disorder. Patterns of benzodiazepine use were influenced by age, gender, and past history of alcohol dependence. CONCLUSIONS: Long-term users of alprazolam/lorazepam seeking treatment for discontinuation had clinically important past and current psychiatric histories. They used a constant or decreasing dose of medication and made attempts to stop their use. Persistent use of alprazolam/lorazepam for therapeutic purposes did not represent abuse or addiction as the terms are usually understood. A substantial proportion of these patients may be receiving appropriate maintenance therapy for a chronic psychiatric condition.

Alprazolam↗
PubMed1994

Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans.

OBJECTIVES: To assess the pharmacologic effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short-term effects of diazepam and alprazolam over a range of doses. METHODS: This was a placebo, within-subject, randomized, double-blind study conducted in 28 male volunteers. They were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish 150 mg secobarbital from placebo and to report positive subjective effects. Subjects randomly received placebo and the two middle doses of diazepam, bretazenil, and alprazolam for the first 7 days of the study and, depending on their clinical response, received either the highest or the lowest dose of each drug for the remaining 3 days. Pharmacologic effects were assessed by use of objective tests (e.g., psychomotor performance), subject-rated questionnaires (e.g., Profile of Mood States), and observer-rated scales. RESULTS: All three drugs were clearly distinguishable from placebo on most measures. Diazepam and alprazolam produced dose-related psychomotor and memory impairment, whereas bretazenil produced a flatter slope. Both alprazolam and diazepam produced dose-dependent increases in subject and observer-rated sedation and liking, whereas bretazenil showed increases compared with placebo, but these effects were not dose dependent. CONCLUSIONS: Results from the study supported the view that bretazenil may have a partial agonist pharmacologic profile. Scores on subjective effects scales considered important for abuse liability assessment suggest a lower abuse liability of bretazenil than diazepam and alprazolam.

Adult↗
PubMed1993

Comparative study on benzodiazepine use in Canada and Chile.

Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and Canada (a developed country) was undertaken. Wholesale data as provided by the Intercontinental Medical statistics and drug import data were used as databases. Data on trends of benzodiazepine use was determined for 5 years using the methodology recommended by the WHO for drug use research, the defined daily dose/1000 inhabitants/day. Total benzodiazepine use was similar in both countries, but Canadian use had increased slowly. Patterns of use, however, differ widely among the two countries. A linear increase of rapidly eliminated benzodiazepines was observed in Canada, whereas the reverse occurs in Chile: the slowly eliminated benzodiazepines are the ones that have increased use. Hypnotic benzodiazepines are used twice as frequently in Canada than in Chile. Striking differences in the use of individual benzodiazepines are observed. Differences in healthcare systems determine wide differences in the way these drugs are prescribed. Demographic characteristics of the two countries also may account for the differences in benzodiazepine use. The authors conclude that, although total benzodiazepine consumption is similar in the two countries, patterns of benzodiazepine use vary widely. The different patterns of use may determine differences in the morbidity rates associated with the use of these drugs.

Anti-Anxiety Agents↗
PubMed1993

Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.

1. In microsomes prepared from three human livers, methadone competitively inhibited the O-demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty-two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O-demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.

Adolescent↗
PubMed1991

Pharmacologic aspects of benzodiazepine tolerance and dependence.

Benzodiazepines, which are among the safest and most effective drugs, possess all the characteristic of abuseable compounds. Although there appear to be differences in potency among compounds and variations in sensitivity among individuals, benzodiazepines have clear reinforcing properties. Tolerance to the depressant effects of benzodiazepines is rapid, but tolerance to the anxiolytic effects develops slowly and to a limited extent. Although abusers use very high doses, most long-term users persist at daily doses in the low therapeutic range (10-20 mg of diazepam or its equivalent) without dose escalation. Physical dependence is a risk associated with long-term use, even at therapeutic doses. The withdrawal syndrome is mild at low doses. Continued self-administration of low therapeutic doses is maintained to alleviate withdrawal symptoms. The advances in the recent understanding of the molecular biology of the benzodiazepine receptor gives hope to the development of new anxiolytic compounds with less dependence liability than the present ones.

Animals↗
PubMed1989

Benzodiazepine use and abuse in Canada.

Benzodiazepines are frequently prescribed, yet the extent of their use in Canada has not been described. Such data would be valuable in assessing patient exposure to benzodiazepines and would provide a context to estimate the risk-benefit ratio of these drugs. Analysis of benzodiazepine sales in 1978-87 in Canada, expressed as the defined daily dose (DDD) per 1000 inhabitants per day, showed that the use of these drugs was stable during the first half of the decade, at 33 DDD/1000 inhabitants per day, then steadily increased from 1983 to 1987, reaching 48 DDD/1000 inhabitants per day in 1987. The total use of slowly eliminated benzodiazepines declined, whereas the overall use of rapidly eliminated benzodiazepines increased linearly. In 1978-83 Canada had the second-lowest total benzodiazepine use among several Western countries. The patterns of use and abuse of rapidly eliminated benzodiazepines in 1978-84 showed a close correlation. Our findings indicate that data on drug use can be monitored and linked to clinical data, providing a mechanism for monitoring the relation between use and related illness.

Benzodiazepines↗
PubMed1989

Clinical pharmacokinetics of non-opiate abused drugs.

The present review discusses the available data on the kinetic properties of non-opiate abused drugs including psychomotor stimulants, hallucinogens and CNS-depressants. Some of the drugs of abuse reviewed here are illicit drugs (e.g. cannabis, cocaine), while others are effective pharmacological agents but have the potential to be abused (e.g. benzodiazepines). Although some of the drugs mentioned in this review have been in use for centuries (e.g. caffeine, nicotine, cocaine, cannabis), knowledge of their kinetics and metabolism is very recent and in some cases still incomplete. This is partially due to the difficulties inherent in studying drugs of abuse in humans, and to the complex metabolism of some of these drugs (e.g. cannabis, caffeine) which has made it difficult to develop sensitive assays to determine biological pathways. Although drugs of abuse may have entirely different intrinsic pharmacological effects, the kinetic properties of such drugs are factors contributing to abuse and dependence. The pharmacokinetic properties that presumably contribute to self-administration and drug abuse include rapid delivery of the drug into the central nervous system and high free drug clearance. Kinetic characteristics also play an important role in the development of physical dependence and on the appearance of a withdrawal syndrome: the longer the half-life, the greater the likelihood of the development of physical dependence; the shorter the half-life, the earlier and more severe the withdrawal. The balance between these 2 factors, which has not yet been carefully studied, will also influence abuse patterns. The clinical significance of kinetic characteristics with respect to abuse is discussed where possible.

Amphetamines↗
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↗
PubMed1987

Drug deprivation and reinforcement by diazepam in a dependent population.

Individuals who were using therapeutic doses (approximately 15 mg diazepam or its equivalent daily) of a benzodiazepine persistently and wished to attempt to stop were recruited into a study offering a medically supported outpatient behavioral treatment with a goal of abstinence. All subjects received the same behavioral treatment that emphasized the development of strategies for coping with abstinence and alternatives to benzodiazepines as a coping mechanism. The goal of abstinence was to be achieved within approximately 8 weeks by means of gradual tapering of the daily dose. Some subjects (Group D, n = 23) were randomly assigned to a condition in which their dose was to be tapered on a regime of active diazepam. Others (Group P, n = 19) were switched to placebo at the first treatment session and "tapered" from this pharmacologically inert substitute for diazepam. Supplies of tablets of each preparation were provided by the experimenters, and subjects were specifically requested to use only those tablets. The principal dependent variable was "supplementation", or use of a benzodiazepine other than that specifically authorized by the therapist. Supplementation was detected by measures of plasma benzodiazepine levels as compared to levels predicted if there had been strict compliance with the therapeutic regime. These comparisons were made by two expert judges who were blind to the subjects' experimental assignment. Self-report of supplementation was also obtained. Plasma level determinations indicated a significantly greater frequency of supplementation (84% versus 33% of subjects) for subjects in Group P.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Benzodiazepines.

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Anti-Anxiety Agents↗
PubMed1986

Withdrawal reaction after long-term therapeutic use of benzodiazepines.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Adolescent↗