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1.
The effects of reboxetine on autonomic and cognitive functions in healthy volunteers 总被引:2,自引:0,他引:2
RATIONALE: Though reboxetine, a selective noradrenaline reuptake inhibitor, causes autonomic and cognitive adverse events there is a paucity of appropriately designed studies on the cognitive and autonomic effects of the drug in the literature. OBJECTIVE: To compare the effects of reboxetine on cognitive and autonomic functions with those of placebo in healthy humans. METHOD: A randomised, double-blind, crossover study of 12 healthy male volunteers aged 25 (21-27; median, range) years. Subjects orally received 4 mg reboxetine and placebo twice daily for periods of 14 days each with at least 14 days in between. Vasoconstrictory response of cutaneous vessels (VR) and skin conductance response (SCR) following sudden deep breath were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for cognitive function. RESULTS: Reboxetine decreased SCR and prolonged the dilation phase of VR (P<0.05). It did not affect cognitive functions such as flicker fusion frequency, choice reaction, memory and psychomotor coordination but increased slow beta (beta1) power density in the qEEG. Tiredness (n=12), dry mouth (n=9), delayed urination (n=3) and constipation (n=1) were noted with reboxetine. CONCLUSION: Sustained peripheral and/or central sympathetic activation accounts for the prolongation of VR. The decrease of SCR and typical side effects suggest a relevant antimuscarinic drug action. Chronic administration of reboxetine at therapeutic doses causes autonomic dysfunction and subjective sedation but does not impair cognitive and psychomotor abilities in healthy humans. 相似文献
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Summary We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design.Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis.Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg).The results suggest that fluvoxamine has some antimuscarinic activity in man, but is considerably less potent in this respect than amitriptyline. 相似文献
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Rationale Though sertraline, a selective serotonin reuptake inhibitor (SSRI), causes autonomic and cognitive adverse events such as
dry mouth and somnolence, there is a paucity of appropriately designed studies on the cognitive and autonomic effects of the
drug in the literature.
Objective To compare the effects of sertraline on cognitive and autonomic functions with those of placebo in healthy humans.
Method A randomized, double blind, cross over study of 12 healthy male volunteers aged 24 (21– 32; median; range) years. Subjects
orally received 50 mg sertraline and placebo once daily for periods of 14 days each with at least 14 days in between. Heart
rate variability (HRV), skin conductance level (SCL) and skin conductance response (SCR) following sudden deep respiration
were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for
cognitive function. Measurements were performed repeatedly before the start of drug administration and on the last treatment
day.
Results Sertraline caused a significant reduction of heart rate and SCL (P<0.05), whereas HRV and SCR were not changed. Cognitive functions such as flicker fusion frequency, memory, choice reaction
time and psychomotor performance were not influenced by sertraline but slow and fast beta power density in the qEEG was increased.
Conclusion Cognitive and psychomotor performance are not altered in healthy humans receiving multiple dosing with sertraline. The observed
decreases in heart rate and SCL may be due to a sympatho-inhibitory effect of sertraline. 相似文献
4.
Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers. 下载免费PDF全文
Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double-blind, balanced cross-over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol- or phenylephrine-evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose-dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol-evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine-evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol-evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine-evoked sweating would be indicative of an alpha-adrenoceptor blocking property of this drug. 相似文献
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Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers
Hou RH Langley RW Szabadi E Bradshaw CM 《Journal of psychopharmacology (Oxford, England)》2007,21(6):567-578
Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property. 相似文献
6.
Summary We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design.Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments.The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures.These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine. 相似文献
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Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D2/D3 autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway).Objectives We investigated the hypothesis that amisulpride, a D2/D3 receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions.Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA.Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels.Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D2/D3 receptors on VTA neurones and in the tuberoinfundibular system. 相似文献
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Samuels ER Hou RH Langley RW Szabadi E Bradshaw CM 《Journal of psychopharmacology (Oxford, England)》2006,20(6):756-770
The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus. 相似文献
10.
盐酸文拉法辛缓释片人体药动学和生物等效性研究 总被引:2,自引:0,他引:2
目的建立测定文拉法辛血浆药物浓度的HPLC荧光检测法,研究盐酸文拉法辛缓释片在人体的药动学和评价生物等效性.方法48例青年健康志愿受试者(单次给药24例,多次给药24例),分别单次和多次交叉口服文拉法辛参比制剂75 mg和受试制剂75 mg,采用HPLC法测定给药后不同时间点血浆中文拉法辛和O-去甲文拉法辛经时血药浓度,采用DAS 2.0进行药动学参数计算.结果单次和多次口服盐酸文拉法辛缓释片的血药浓度-时间曲线符合一室开放模型.单次口服受试制剂和参比制剂后文拉法辛的Tmax分别为(6.5±1.9)与(6.3±1.4)h,t1/2分别为(11.6±4.9)与(11.7±4.3)h,AUC0~1分别为(1 840.0±1 153.1)和(1 956.O±1 201.2)μg·h·L-1;O-去甲文拉法辛的Tmax分别为(12.0±6.0)与(10.3±6.1)h,t1/2分别为(18.9±4.8)与(20.3±6.2)h,AUG0-t分别为(1 356.8±344.1)和(1 382.8±287.3)μg·h·L-1;文拉法辛和O-去甲文拉法辛的生物利用度分别为(94.3±13.3)%和(99.3±20.4)%.多次口服受试制剂和参比制剂6 d后文拉法辛的AUCss分别为(1 488.9±863.3)和(1 630.7±962.2)μg·h·L-1,Tmax分别为(7.0±1.6)与(6.7±1.8)h,DF分别为(114.63±27.05)和(110.94±24.25);O-去甲文拉法辛的AUCss分别为(528.3±220.6)和(568.3±251.1)μg·h·L-1,Tmax分别为(7.7±2.1)与(7.3±1.9)h,DF分别为(70.12±21.63)和(71.67±24.27);文拉法辛和O-去甲文拉法辛的生物利用度分别为(93.2±17.7)%和(95.9±17.0)%.结论经方差分析和t检验,证明两制剂生物等效. 相似文献
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Two single doses (300 and 600 mg) of fengabine, a novel antidepressant, a single dose (50 mg) of amitriptyline, and a single dose of placebo were taken by sixteen male healthy volunteers (18–30 years), in weekly experimental sessions, according to a balanced double-blind cross-over design. In Part A (eight subjects) subjective mood state, psychomotor performance and some baseline autonomic functions were measured before, and 1, 3 and 5 hours after drug taking. In Part B, cholinoceptor-mediated tissue responses (pilocarpine-evoked miosis and carbachol-evoked sweating) were measured two and a half hours after drug taking. Fengabine and placebo did not affect any of the test results, whereas amitriptyline had effects consistent with the sedative (reduction in alertness, impairment of psychomotor performance) and antimuscarinic (reduction in salivation and carbachol-evoked sweating) properties of the drug. 相似文献
12.
Müller U Clark L Lam ML Moore RM Murphy CL Richmond NK Sandhu RS Wilkins IA Menon DK Sahakian BJ Robbins TW 《Psychopharmacology》2005,182(2):205-213
Rationale Guanfacine is an α2-adrenergic receptor agonist that has been shown to have beneficial effects on working memory and attentional functions in
monkeys and in patients with attention deficit hyperactivity disorder.
Objectives The aim of this study was to further investigate the cognitive-enhancing properties of guanfacine using an established battery
of tasks measuring executive and memory functions.
Methods Sixty healthy male volunteers were randomised into three groups. Cognitive testing was performed from +2 to +4 h after double-blind
administration of a single oral dose of 1 or 2 mg of guanfacine or placebo.
Results Systolic blood pressure was significantly reduced by both doses of guanfacine at the end of the testing session. There were
no statistically significant effects on any of the cognitive measures. Two trend effects were observed with poorer performance
on digit span backward and slower ‘Go’ reaction times after guanfacine.
Conclusion This study found no improvement of prefrontal memory or executive functions after guanfacine. Negative effects on blood pressure
and trend effects on digit span backward and go reaction time indicate a mild sedative effect of guanfacine at these doses,
possibly via mechanisms of autoreceptor down-regulation. 相似文献
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Blier P Saint-André E Hébert C de Montigny C Lavoie N Debonnel G 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2007,10(1):41-50
Venlafaxine is generally considered to be a dual 5-HT and NE reuptake inhibitor when it is used at doses above 75 mg/d in humans. While its 5-HT reuptake-inhibiting property has been demonstrated, some controversy still exists regarding the doses of venlafaxine required to inhibit NE reuptake. Healthy male volunteers received, on a double-blind basis, paroxetine (20 mg/d), desipramine (100 mg/d), nefazodone (300 mg/d), or venlafaxine (150 or 300 mg/d) in the last 5 d of a 7-d period of administration. Inhibition of 5-HT reuptake was estimated by determining the degree of depletion of whole-blood 5-HT, while that of NE was assessed by measuring the attenuation of the systolic blood pressure increases produced by intravenous injections of tyramine. Paroxetine, both regimens of venlafaxine, and to a lesser extent desipramine significantly decreased whole-blood 5-HT content. Nefazodone failed to produce any significant change. Desipramine abolished the tyramine pressor response, whereas all other drug regimens left this parameter unaltered. Venlafaxine and paroxetine acted as potent 5-HT reuptake inhibitors in the present study. In contrast, neither the moderate nor the high dose of venlafaxine displayed any significant inhibiting activity in this model assessing NE reuptake in peripheral NE terminals. The validity of the model was confirmed by the potent inhibitory action of desipramine on NE reuptake. While the reasons for this unexpected lack of action remain unclear, venlafaxine appeared to be an effective NE reuptake agent in depressed patients using the same approach. 相似文献
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Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers 总被引:3,自引:0,他引:3 下载免费PDF全文
Samuels ER Hou RH Langley RW Szabadi E Bradshaw CM 《British journal of clinical pharmacology》2007,64(5):591-602
AIMS: To investigate the effects of the D2-receptor agonist pramipexole with and without the co-administration of the peripherally acting D2-receptor antagonist domperidone on measures of alertness, autonomic and endocrine function. METHODS: Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons. RESULTS: The pre-post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F(3,45) = 8.39, P < 0.001), initial diameter of the light reflex response (F(3,42) = 3.78, P < 0.05), and light (F(3,45) = 5.21, P < 0.005) and dark (F(3,45) = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations. CONCLUSIONS: The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2-receptors. 相似文献
15.
Rationale: Antidepressant drugs are thought to enhance serotonergic neurotransmission through postsynaptic 5-HT1A receptors. This effect is delayed in animals and may be paralleled by a delay in the onset of a clinical response in humans.
In humans, the growth hormone (GH) response to intravenous l-tryptophan (IV l-TRP) is blocked by the 5-HT1A antagonist pindolol and the prolactin response is blunted. Both are therefore thought to be a useful measure of 5-HT1A receptor function. Clomipramine has previously been found to enhance the GH and prolactin responses to IV l-TRP after only 2 h. Objective: The purpose of this study was to use this method to investigate the effects of newer antidepressants on 5-HT1A receptor-mediated function. Methods: Twelve healthy male volunteers took part in a random order, double blind study, in which 18.75 mg venlafaxine, 5 mg paroxetine
or placebo was administered 3 h before infusion of l-TRP. Results: Pretreatment with venlafaxine significantly enhanced the growth hormone (GH) response to the infusion compared with pretreatment
with placebo. There was no significant difference between the GH response following paroxetine compared with placebo or with
venlafaxine. Conclusions: The data suggest enhancement of transmission through postsynaptic 5-HT1A receptors by venlafaxine but not paroxetine, after only 3 h.
Received: 11 January 1999 / Final version: 17 May 1999 相似文献
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Comparison of the effects of ranitidine, cimetidine and thioridazine on psychomotor functions in healthy volunteers 下载免费PDF全文
N Theofilopoulos E Szabadi C M Bradshaw 《British journal of clinical pharmacology》1984,18(2):135-144
Eight healthy male volunteers participated in four experimental sessions in which they ingested one of the following drugs: ranitidine hydrochloride (150 mg), cimetidine hydrochloride (400 mg), thioridazine hydrochloride (50 mg), placebo (lactose). Drugs were allocated to subjects and sessions in a double-blind fashion, according to a balanced cross-over design. The subjects' mood state and psychomotor performance were assessed 1 and 3 h after drug taking. Mood state was measured using a battery of visual analogue scales, and psychomotor performance using pencil-and-paper tests, critical flicker fusion frequency, wire-maze tracing and tapping. Ranitidine and cimetidine had no significant effect on subjectively rated alertness, whereas thioridazine caused a significant decrease in alertness. Ranitidine and cimetidine had no significant effect on performance on the pencil-and-paper tests (digit cancellation, digit symbol substitution, symbol copying), whereas thioridazine caused a significant decrement on these tests. Ranitidine and cimetidine had no significant effect on critical flicker fusion frequency, wire-maze tracing, and tapping rate. Thioridazine caused a significant impairment of psychomotor performance as evidenced by all the instrumental tests. It is concluded that, in contrast to thioridazine and similarly to cimetidine, ranitidine has little effect on subjectively rated alertness and psychomotor performance in healthy volunteers. 相似文献
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Twenty healthy young adults completed a series of nonverbal and problem solving tasks in a repeated measures design involving placebo and 0.6 mg scopolamine, administered by subcutaneous injection. Subjects completed the test battery under standard presentation conditions and with concurrent articulation, which precludes verbal recoding of test material. Under standard presentation conditions, scopolamine significantly impaired performance on the problem solving task and on tasks of visuo-spatial and spatial memory; memory for abstract shapes was not impaired. Concurrent articulation impaired performance on the shape recognition and interacted with drug treatment on the problem solving task. The results suggest that scopolamine impairs working memory, and that the decrement is at the level of the central executive mechanism rather than the subsystems which it controls. 相似文献
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Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers 总被引:4,自引:0,他引:4
DeVane CL Donovan JL Liston HL Markowitz JS Cheng KT Risch SC Willard L 《Journal of clinical psychopharmacology》2004,24(1):4-10
An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction. This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05). For nefazodone, a statistically significant inhibition was observed (P < 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4. 相似文献