ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Psychosis frequently occurs in women of child-bearing potential who may have unplanned pregnancies. Understanding the risk of prenatal antipsychotic exposure can be of benefit in selecting therapies. The authors evaluated thein uteroand lactation exposure effects of olanzapine, a novel antipsychotic that is used in treating schizophrenia, bipolar disorder, and other conditions and that may have expanded use in the childbearing population. All prospectively and retrospectively ascertained pregnancy reports were collected as a registry in the Lilly Worldwide Pharmacovigilance Safety Database. Outcomes were available from 23 prospectively ascertained olanzapine-exposed pregnancies. Spontaneous abortion occurred in 13%, stillbirth in 5%, major malformation in 0%, and prematurity in 5%, all within the range of normal historic control rates. There were 11 retrospectively ascertained cases of pregnancy. Two retrospectively ascertained cases of lactation exposure did not suggest infant risk. The early experience with olanzapine use in pregnancy and lactation is encouraging in that no obvious added risk to the fetus or infant was observed. Additional cases of pregnancy and lactation exposure need to be evaluated to determine whether these early findings are representative of the risks of olanzapine exposure to the fetus and infant. At this time, olanzapine should only be used during pregnancy and lactation when the potential benefit justifies the potential risk to the fetus or infant.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The therapeutic spectrum of nemonapride, a new substituted benzamide, and its relationship with plasma concentrations of the drug and prolactin were investigated by a fixed-dose study (18 mg/day for 3 weeks) in 31 patients with acutely exacerbated schizophrenia. Of 31 patients, 25 (80.6%) were responders who showed a reduction in symptoms (percentage of improvement) of 50% or more after 3 weeks. The mean values of percentage of improvement in scores on the total Brief Psychiatric Rating Scale (BPRS) and the five subscale symptoms were 71.5% for total, 73.2% for Positive, 86.0% for Excitement, 53.9% for Negative, 84.2% for Cognitive, and 67.5% for Anxiety-Depression. Responders had higher percentage of improvement in positive (84.6 ± 17.0†% vs. 25.9 ± 15.7%;p< 0.001) and anxiety-depression (76.9 ± 18.8% vs. 28.5 ± 39.9%;p< 0.005) symptoms than did nonresponders after 3 weeks. The percentage of improvement in total BPRS after 2 weeks was well correlated with that after 3 weeks (Spearman rank correlation coefficient:rs= 0.711;p< 0.01). There was an inverted U-shaped relationship between plasma drug concentrations (nemonapride plus desmethylnemonapride) and percentage of improvement in total BPRS symptoms after a 3-week treatment (y = 46.9 + 73.9x − 44.2x2;p< 0.001). These findings suggest that nemonapride has a broad therapeutic spectrum in the treatment of acute schizophrenia. The improvements in scores for the Positive and Anxiety-Depression subscale symptoms are regarded as determinant factors for total response to nemonapride. An assessment of clinical status after 2 weeks and plasma drug monitoring may be useful for the prediction of the final outcome for patients.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Obsessive-compulsive-related disorders are frequently comorbid with schizophrenia. The existence of obsessive and compulsive symptoms in patients with schizophrenia represents one of the most severe types of psychotic disorders and may predict a poor prognosis in most cases. Previous pilot studies and case reports have shown that the condition of some patients with schizophrenia did not exacerbate and even improved when serotonin reuptake inhibitors (SSRIs) were added to their standard neuroleptic regimen. The aim of this study was to evaluate the efficacy of a combination treatment of an SSRI (fluvoxamine) and standard neuroleptics for the treatment of obsessive-compulsive (OC) symptomatology in patients with schizophrenia compared with administration of neuroleptics only. Thirty inpatients who met DSM-IV criteria for schizophrenia and also had prominent OC symptoms were randomly divided into two groups. Fourteen patients were treated with conventional neuroleptics and fluvoxamine in doses of 100 to 200 mg/day for 8 weeks. Sixteen patients comprised a control group and received only their previous therapeutic neuroleptic therapy. The patients were assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Scale (CGI) at baseline and endpoint. Side effects were assessed weekly. The data were analyzed using an analysis of variance. A considerable reduction in PANSS (34.3%) and Y-BOCS (29.4%) scores was noted, and CGI scores decreased moderately in both groups. None of the patients showed an acute exacerbation at the end of the study. Side effects were mild and easily tolerated in most patients. This open, randomized, controlled study reveals that coadministration of fluvoxamine, an SSRI, and neuroleptics in patients with schizophrenia and OC symptoms was associated with specific improvements of these symptoms. Thus, the use of an SSRI in treating a patient with schizophrenia and OC symptomatology may be warranted and safe. Other implications of the findings, including general safety of the combined pharmacotherapy and the use of new antipsychotic medications, are also discussed.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Antidepressants can be administered by different routes. Advantages for either the oral or the intravenous administration have been suggested from pharmacokinetic as well as from clinical points of view. Controlled comparison studies of the two routes do not provide unequivocal recommendations. In this investigation, amitriptyline was studied over a 4-week period consisting of a 2-week, double-blind/double-dummy phase with either oral (150 mg/day), high-dose intravenous (150 mg/day), or medium-dose intravenous (100 mg/day) treatment and a 2-week phase of open oral treatment in 80 patients with major depression. A psychopathologic assessment was made using the Hamilton Rating Scale for Depression, the Clinical Global Impressions Scale, the von Zerssen's "Befindlichkeitsskala," an adjective checklist, and a Visual Analog Scale. No significant differences were found concerning the mean scores of the rating scales or time of onset of action in the physicians' ratings. In the patients' self-ratings, there was an earlier therapeutic effect in the high-dose intravenous group. The number of improvers after 7 days was significantly higher in the high-dose intravenous group compared with both other groups. After 14 days, no significant differences in the numbers of improvers and responders between groups were detected. The results of this study do not clearly favor one of the tested options. The main differences found in this study seem to be dose-related rather than differentiating between oral and intravenous routes of administration.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Fluoxetine (FLX) has a unique pharmacokinetic profile. Its major metabolite, norfluoxetine (NFLX), possesses FLX's antidepressant efficacy and a half-life of 7 to 15 days, suggesting the possibility of nonstandard dosing strategies. This study examined the tolerability of a weekly dose and its equivalence to daily dosing of FLX for the continuation phase of treatment for major depressive disorder (MDD). One hundred fourteen subjects initially received open-label treatment with 20 mg of FLX daily for 7 weeks. Subsequently, 70 subjects with a score on the Hamilton Rating Scale for Depression (HAM-D) of 12 or less were randomly assigned in a double-blind design to one of three treatment groups: 20 mg FLX daily (N = 21), 60 mg FLX weekly (N = 28), or placebo (N = 21) and were followed for 7 weeks. HAM-D scores and blood levels of FLX and NFLX were analyzed using a repeated-measures analysis of variance. During the double-blind phase, blood levels for both FLX and NFLX differed across the treatment groups, yet no statistically significant difference in HAM-D scores was observed. There was no difference in the dropout rate across the groups. Subjects could not correctly identify the treatment group into which they were assigned. Weekly dosing of FLX seems to be well tolerated and possibly as effective as daily dosing in maintaining the therapeutic response in subjects with MDD.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Propafenone is mainly metabolized by CYP2D6 to form 5-hydroxypropafenone (5-OHP) and to a minor extent by CYP1A2 and CYP3A4 to formN-depropylpropafenone (N-DPP). Thein vitroinhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on the formation of both metabolites was studied, using human liver microsomes. The 5-OHP formation from racemic propafenone and from its individual enantiomers followed one-enzyme Michaelis-Menten kinetics. Incubation with the racemate yielded a mean Vmaxof 64 pmol · min−1· mg−1and a meanKmof 0.12 μM (N = 3). Stereoselectivity in VmaxandKmvalues was observed, with (S)-propafenone displaying higherKmand Vmaxvalues. N-DPP formation from racemic propafenone followed one-enzyme Michaelis-Menten kinetics and yielded a mean Vmaxof 403 pmol · min−1· mg−1and a meanKmof 116 μM (N = 3). No stereoselectivity in propafenone N-dealkylation was observed. The influence of SSRIs and quinidine, a prototypical CYP2D6 inhibitor, on propafenone 5-hydroxylation was investigated. Quinidine was the most potent inhibitor, followed by fluoxetine, norfluoxetine, and paroxetine. Sertraline, desmethylsertraline, and fluvoxamine had only a moderate inhibitory effect, whereas citalopram displayed slight or no inhibition when racemic propafenone was used as substrate. MeanKivalues of quinidine, fluoxetine, norfluoxetine, and paroxetine were 0.13, 0.33, 0.55, and 0.54 μM, respectively (N = 3). Quinidine and paroxetine were also tested as inhibitors using the individual enantiomers, but no stereoselectivity was observed. Among the SSRIs tested, only fluvoxamine substantially inhibited propafenone N-dealkylation with a mean IC50of 7.0 μM (N = 3). There was a more pronounced inhibitory effect of fluvoxamine on (R)-propafenone than on (S)-propafenone N-dealkylation. In conclusion, thesein vitrodata suggest that anin vivointeraction between propafenone and the SSRIs, fluoxetine and paroxetine, can be expected, which can lead to clinically relevant β-blockade and an increased risk of side effects in the central nervous system. An interaction with fluvoxamine may be of importance in poor metabolizers for CYP2D6.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p< 0.01) and resulted in a decrease in the positive (e.g., "high,"p< 0.05) and negative (e.g., nausea,p< 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p< 0.01), and it decreased positive codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Neuropeptides of the adrenocorticotropin/melanocorticotropin (ACTH/MSH) family are most potent modulators of cognitive function. Their neurobehavioral activity is principally encoded in the 4-10 fragment of the ACTH/MSH molecule; in humans, it has been shown to pertain primarily to functions of attentive stimulus/response processing. The aims of this study were (1) to examine the effects of ACTH 4-10 on event-related brain potentials (ERPs) and behavioral indicators of stimulus encoding within the working memory; (2) to compare the effects after a single dose and after prolonged treatment with ACTH 4-10; and (3) to compare the effects of ACTH 4-10 with those of desacetyl-α-MSH (i.e., ACTH 1-13 amide), which, like ACTH 4-10, binds to the known brain melanocortin receptors (MC-Rs) but with distinctly higher affinity. Double-blind, placebo-controlled experiments were performed in 60 healthy control subjects. The authors monitored ERPs and reaction times while these subjects performed an auditory vigilance task ("oddball"). Recall was tested on a verbal short-term memory task including different word categories (neutral, rare, food, sex). After a single (1 mg) as well as prolonged intranasal administration (1 mg/day over a period of 6 weeks), ACTH 4-10 enhanced the positive slow wave in ERPs to target stimuli of the vigilance task (p< 0.05), but left classic P3 unaffected. Moreover, single-dose and prolonged administration of ACTH 4-10 increased the rate of false responses during vigilance (p< 0.01). In the short term, ACTH 4-10 also impaired recall of neutral words (p< 0.05). Equimolar doses of desacetyl-α-MSH did not influence ERPs, neither after a single dose nor after prolonged treatment. Similar to ACTH 4-10, desacetyl-α-MSH increased the error rate during vigilance and acutely impaired the recall of neutral words. The increase in ERP slow-wave positivity, in conjunction with behavioral impairments after treatment with ACTH 4-10, complemented previous results of inferior focusing of attention and a less concise structure of thought after administration of ACTH 4-10. The changes indicated an impairment in differential processing of relevant versus irrelevant contents within the working memory, and, in this regard, might mimic aspects of psychopathologic disturbances of attention and thought processes. Their persistence after prolonged treatment with ACTH 4-10 suggests an activation of mechanisms subserving the consolidation of the peptide's effects. The poor efficacy of desacetyl-α-MSH suggests that the known MC-Rs may be irrelevant for mediating cognitive effects of this neuropeptide family.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug of increasing use among youth because of its apparent entactogenic properties, such as euphoria, friendliness, closeness, and empathy. However, experimental studies have shown MDMA to be neurotoxic. Data on pharmacologic actions of MDMA in humans are limited. The authors conducted a randomized, double-blind, crossover, controlled trial to assess psychomotor performance and subjective effects in eight healthy male volunteers. MDMA was given in the same range of doses used for recreational purposes (75 and 125 mg). Amphetamine (40 mg) and placebo were used as reference compounds. For the digitsymbol substitution test (DSST), MDMA-125 produced a mild decrease in responses, and amphetamine produced a mild improvement. For the Maddox wing device, MDMA-125 induced esophoria compared with the other drug conditions. MDMA-125 and MDMA-75 produced increases in feelings of euphoria and well-being, as noted by increases in scores on the Addiction Research Center Inventory (ARCI) MBG and A scales, as well as scores of "stimulated," "good effects," "liking," and "high" on the visual analog scales. Amphetamine administration induced similar effects. At the same time, MDMA-125 enhanced sedation- and dysphoria-related effects (ARCI-PCAG and LSD, "confusion," "drunken," and Profile of Mood States Confusion scale). Mild changes in some body perception-related feelings were also reported after MDMA use, but hallucinations or psychoses were not present. In summary, the short-term administration of MDMA produced marked euphoria, a slight impairment in the performance of psychomotor tasks, and mild changes in body perceptions without hallucinations. These data support the abuse liability of MDMA.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID