Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers

Single-dose pharmacokinetics of alprazolam was studied in 42 normal male volunteers (14 Caucasians, 14 American-born Asians, and 14 foreign-born Asians), after both oral and parenteral (IV) administration of a small dose (0.5 mg) of the test drug. Asians manifested significantly higher C _max, larger AUC, slower CL and longer t 1/2 under both testing situations. When body surface area was used as a covariate, these cross-ethnic differences remained statistically significant (except C _max) after oral but not IV drug administration. There were no differences between the two Asian groups in any of these parameters examined in this study. These results confirmed previous observations of ethnic differences in the pharmacokinetic response between Asians and Caucasians and suggested that smaller doses of alprazolam may be required for Asians for similar clinical effects as compared to their Caucasian counterparts.     

A dose response study of the hypnotic effectiveness of alprazolam and diazepam in normal subjects

One group of eight normal young males was administered three doses of alprazolam (0.25, 0.5 and 1.0 mg) and placebo, while a second group of eight normal young males was given three doses of diazepam (2, 5, and 10 mg) and placebo in the same design. All subjects slept in the sleep laboratory for 10 nights, 2 consecutive nights each week for 5 consecutive weeks. The first 2 nights served as adaptation. During the next 4 weeks subjects received a random dose of alprazolam (or placebo) or a random dose of diazepam (or placebo) each week. Similar dose-related benzodiazepine effects were found on sleep with both medications. Alprazolam reduced percent stage 4 and REM sleep and increased stage 2 sleep and latency to REM. Diazepam decreased percent stage 1 and increased percent stage 2 sleep. No drug by dose interactions were found. It was concluded that, while both drugs had similar effects on sleep, alprazolam showed significant effects on REM sleep parameters and might be evaluated for possible antidepressant effect.Supported by the Upjohn Company     

Effects of alprazolam and diazepam on the daytime sleepiness of non-anxious subjects

Eighteen non-anxious volunteers underwent sleep recordings and daytime tests of sleepiness, performance, and mood while receiving, either alprazolam 0.5 mg b.i.d. or diazepam 5 mg b.i.d. for 7 consecutive days. Recordings and tests were done before treatment and on the 1st and 7th days of treatment. Nocturnal sleep changes were similar for both groups; there were no statistically significant changes in mood. However, levels of daytime sleepiness differed. Alprazolam subjects showed more daytime sedation than diazepam subjects on treatment day 1, but showed a significant decreased in Day 1–7 daytime sedation. Although diazepam subjects were less sedated at the onset, they showed no tolerance to this effect; thus by treatment day 7, the two groups did not differ in levels of daytime sleepiness. Results suggested that tolerance to alprazolam's sedative effects (which develops during the 1st week of treatment) may be separable from tolerance to its antianxiety effects (which develops after at least 4 weeks). As daytime sedation is common and potentially dangerous with most anxiolytics, selective tolerance to this side effect is highly desirable.     

慢性肾脏病患者血清甲状腺激素测定的临床意义

目的观察慢性肾脏病(CKD)患者血清甲状腺激素(TH)的变化。方法选择50例CKD患者作为观察组(CKD组),50例同期进行体检的健康人作对照组,测定血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺素(TSH)浓度及肾功能。结果 CKD组FT3(1.76±0.23)pmol/L、FT4(7.26±1.38)pmol/L,明显低于对照组的(5.42±0.56)pmol/L、FT4(16.54±3.73)pmol/L(P<0.05)。CKD组FT3、FT4分别与血尿素氮、肌酐呈负相关(P<0.01)。结论动态监测CKD患者血清TH的变化,对于判断患者的病情轻重与预后具有重要的参考价值。     

Comparative pharmacokinetics and pharmacodynamics of lorazepam,alprazolam and diazepam

The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.     

Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo

CD-1 mice received single intraperitoneal (IP) doses of caffeine-sodium benzoate (caffeine doses: 0, 20 and 40 mg/kg) followed by injections of alprazolam-propylene glycol (0, 0.05, and 2 mg/kg, IP) to determine brain concentrations, effects on in vivo receptor binding of a specific high-affinity benzodiazepine receptor ligand [³H]Ro15-1788, and effects on motor activity over a 1-h period. A behavioral monitoring device, using infrared sensors, measured horizontal and ambulatory activity. Caffeine produced significant increases in all motor activity measures as compared to vehicle treatment, with low dose caffeine (with brain concentrations of 13 µg/g) stimulating activity to a greater degree than the high dose (with brain concentrations of 30 µg/g). The overall effect of caffeine on benzodiazepine receptor binding was not significant. Alprazolam significantly diminished motor activity and altered benzodiazepine receptor binding. Low dose alprazolam increased binding, while the high dose diminished it. Caffeine and alprazolam antagonized each other's behavioral effects in this study, but did not alter each other's uptake into brain. Alprazolam's antagonism of caffeine-induced motor stimulation was associated with decreases in receptor binding, whereas caffeine's reversal of alprazolam-induced motor depression was not associated with any changes in binding. The lack of a clear association between drug effects on benzodiazepine binding and on motor activity suggests that behavioral effects of caffeine and alprazolam may be mediated by other sites in addition to the benzodiazepine receptor.Supported in part by Grants MH-34223, AG-00106, and DA-05258 from the Department of Health and Human Services     

The effects of desipramine on thyroid hormone concentrations in rat brain

The effects of the antidepressant desipramine on the tissue concentrations of thyroxine and triiodothyronine in 9 different regions of the brain and also in the pituitary and liver were investigated in male rats. The investigations were carried out at three different times of the light/dark cycle: 5 a.m., 1 p.m. and 11 p.m. After fourteen days' treatment with 20 mg/ kg/day desipramine by gavage the concentrations of triiodothyronine in the frontal and parieto-occipital cortex were significantly higher than in the saline-treated controls, those in the hippocampus lower and those in the 6 remaining brain regions the same. In 8 areas of the brain the concentrations of thyroxine were lower in the desipramine-treated rats and the tissue ratios of triiodothyronine to thyroxine were enhanced in 6 regions. These effects are most likely the result of the action of desipramine on the activity of the isoenzyme 511 deiodinase. This enzyme catalyzes the deiodination of thyroxine to triiodothyronine in rat brain and its activity has recently been reported to be enhanced by desipramine. The observed effects were dose-dependent and also strongly dependent upon the time within the 24 h light/dark cycle at which the hormone concentrations were measured. No effects of desipramine were seen in the pituitary or liver after 14 days' treatment, or in various areas of the central nervous system 24 h after administration. In view of the psychotropic properties of thyroid hormones, it seems possible that the observed increases in triiodothyronine concentrations, particularly in cortical areas, are involved in the mechanisms of action of desipramine.     

Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology

A symposium at the 2003 Annual Meeting of the Society of Toxicology brought together an expert group of endocrinologists to review how non-reproductive hormones can affect the endocrine system. This publication captures the essence of those presentations. Paul Cooke and Denise Holsberger recapitulate the evidence of how thyroid hormones affect male and female reproduction, and reproductive development. Ray Witorsch summarizes the many effects of glucocorticoids on the reproductive system. Finally, Paul Sylvester reviews the mechanism of action of prolactin, and reminds us that this ancient hormone has many functions beyond lactation.     

Effects of manganese ions on thyroid function in rat

Rats were treated with MnSO₄, H₂O (1 mg/100 g/day, SC) for a period of 5 weeks. Thyroxine (T₄) and triiodothyronine (T₃) levels were measured in thyroid by radioimmunoassay. T₄, T₃ and thyroid-stimulating hormone (TSH) levels were also estimated by radioimmunoassay in serum. Manganese treatment produced no change in thyroid T₄ and T₃ levels but induced a significant decrease in serum T₄, T₃ and TSH levels. This decrease can be interpreted as the result of a pituitary alteration which appears to be related to the high accumulation of manganese in the pituitary gland.     

肺结核强化抗痨临床转归与甲状腺激素变化的关系

目的观察肺结核强化抗痨治疗临床转归与血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、反三碘甲状腺原氨酸(γT3)水平的关系。方法对71例肺结核患者强化抗痨治疗前后血清FT3、FT4、γT3进行动态观察。结果强化治疗后好转组35例的血清FT3、FT4分别由(4.87±3.06)pmol/L、(15.55±5.77)pmol/L升至(5.79±3.31)pmol/L、(18.27±5.36)pmol/L,γT3由(0.42±0.18)nmol/L降至(0.29±0.12)nmol/L;恶化或无变化组36例的血清FT3、FT4分别由(3.56±2.38)pmol/L、(12.74±5.19)pmol/L降至(3.26±1.44)pmol/L、(11.63±4.96)pmol/L,γT3由(0.46±0.28)nmol/L升至(0.73±0.29)nmol/L。结论动态观察血清FT3、FT4、γT3的变化对评价强化抗痨疗效有一定临床意义。     

急性期脑出血患者血清及脑脊液甲状腺激素的动态观察

目的　观察急性期脑出血患者血清及脑脊液 (CSF)甲状腺激素水平变化 ,探讨其发生机制及临床意义。方法　用放射免疫法对实验室、对照组血清及 CSF的 T3、FT3、T4、FT4、TSH分别进行检测。结果　在脑出血发病后 3d,T3、FT3显著降低 (P<0 .0 5 )。 7d开始升高 ,14d后接近对照组水平。T4、FT4、TSH变化不显著(P>0 .0 5 )。结论　急性脑出血患者血清及 CSF中 T3、FT3水平增高可能与急性期脑出血 (特别是脑水肿高峰期 )出现的内分泌紊乱有关 ;甲状腺激素水平变化与脑出血部位及预后有关     

糖尿病与甲状腺激素水平异常相关性研究

目的 探讨糖尿病与甲状腺激素的关系.方法 选取糖尿病患者98例,另选取健康人群40例作为对照组.抽取受检者空腹静脉血5ml,测定其T3、T4、FT3、FT4、TSH、rT3水平,并分析与糖尿病类型、病情、病程的关系.结果 (1)糖尿病与对照组的关系:Ⅰ型DM组和2型DM组T3、T4、FT3、FT4水平均低于对照组,rT3高于对照组(P＜0.05);1型DM组T3、T4、FT3、FT4水平均低于2型DM组,rT3高于2型DM组(P＜0.05).(2)病情与TH关系:7％ ～ 10％组、＞10％～13％组和HbA1c＞ 13％组的T3、FT3及TSH均低于HbA1c ＜7％组(P＜0.05).(3)病程与TH关系:随着病程的延长T3、FT3呈下降趋势,rT3呈上升趋势(P＜0.05).结论糖尿病患者存在甲状腺激素水平异常,监测其甲状腺激素对评价患者糖尿病病情及病程具有重要意义.     

Treatment of depressive outpatients with lorazepam,alprazolam, amytriptyline and placebo

This randomized double-blind study in 342 mildly to moderately depressive outpatients investigated the antidepressant effectiveness and speed of action of lorazepam, alprazolam and amitriptyline versus placebo. Six weeks of drug treatment were followed by a drug taper period, a control period with placebo and a control period without placebo, of 2 weeks duration each. Clinical improvement was assessed by rating scales (Clinical Global Impressions, Hamilton Rating Scales for Depression and Anxiety) and patient's self-ratings (Patient's Global Impressions, Self-rating Depression Scale and Visual Analogue Scale). At the end of week 6 all active drugs showed similar efficacy which was significantly superior to placebo. Compared to placebo, onset of efficacy was earlier on benzodiazepines than on amitriptyline. While tapering by decreasing the dosage, replacing drug with placebo and finally discontinuing placebo, clear withdrawal phenomena were not seen, but 20% of patients, equally distributed to all treatment groups, did not want to stop taking tablets after replacing drug with placebo. Drop-out rate during the treatment period was very low (9%). Significantly interfering adverse effects were seen in 27 patients, without predominance in one of the active drug groups.     

拉米夫定对乙肝肝硬化患者血清甲状腺激素水平的影响

目的探讨拉米夫定对乙肝肝硬化患者血清甲状腺激素水平的影响。方法 79例HBV DNA阳性乙肝肝硬化患者接受拉米夫定治疗52周,治疗前后检测血清T3、T4、FT3、FT4、TSH。结果拉米夫定治疗52周后HBV DNA转阴组血清T3、T4、FT3、FT4水平较治疗前和HBV DNA未转阴组均有明显改善(P<0.05)。结论乙肝肝硬化患者在拉米夫定抗乙肝病毒取得较好疗效的同时可以显著改善血清甲状腺激素水平。     

慢性阻塞性肺疾病患者营养状况与瘦素及肿瘤坏死因子α和甲状腺激素关系的研究

目的探讨血清瘦素、肿瘤坏死因子α（TNF—α）和甲状腺激素在慢性阻塞性肺疾病（COPD）患者营养不良发生中的意义。方法观察COPD临床稳定期患者148例,根据体质指数（BMI）、理想体质量百分比（NW％）、三头肌皮皱厚度（TSF）、上臂中点臂围（MAC）、血清白蛋白（ALB）、总淋巴细胞（LYM）等营养参数,分为COPD营养不良组（COPDⅠ组）47例,COPD非营养不良组（COPDⅡ组）101例,另选健康人30例为对照组。采用双抗体夹心酶联免疫吸附法检测血清瘦素、TNF-α,采用放射免疫法测定甲状腺激素（T3、T4、FT3、FT4、TSH）,并探讨上述因素在COPD营养不良患者中的作用及相互之间的相关性。结果COPDI组BMI、NW％、TSF、MAC、ALB、LYM与COPDⅡ组、对照组比较差异均有统计学意义（P〈0．01）,COPDⅡ组与对照组比较差异无统计学意义（P〉0．05）;COPDⅠ组瘦素水平分别与COPDⅡ组、对照组比较差异均有统计学意义（P〈0．01）,COPDⅡ组与对照组比较差异无统计学意义（P〉0．05）;COPDⅠ组、COPDⅡ组TNF-α水平分别与对照组比较差异有统计学意义（均P〈0．01）,而COPDⅠ组与COPDⅡ组比较差异无统计学意义（P〉0．05）;COPDI组T3、T4分别与COPDⅡ组、对照组比较差异有统计学意义（均P〈0．01）;COPDⅡ组T4与对照组比较差异有统计学意义（均P〈0．01）。COPDⅠ组、COPDⅡ组BMI、NW％、TSF与瘦素水平呈正相关（P〈0．01）,瘦素水平与TNF—α、TSH呈正相关（P〈0．05）。结论COPD患者营养不良与血清瘦素水平、TNF-α及甲状腺激素有关,瘦素受TNF—α系统调控,瘦素与下丘脑-垂体-甲状腺轴之间存在相互调节关系,三者共同参与了COPD患者营养不良的发生。     

Effects of alprazolam on the acoustic startle response in humans

In the present study, we assessed the effects of the potent benzodiazepine alprazolam on the human acoustic startle response in healthy volunteers. Eight undergraduate students received single oral doses of placebo and alprazolam 2 mg on 2 separate days, according to a double-blind balanced crossover design. Electromyographic activity of the orbicularis oculi muscle was recorded 5, 7 and 11 h after drug administration. At each recording time, subjects received 21 acoustic stimuli (1 KHz, 116 dB, 50 ms duration) separated by variable intervals (8–30 s, mean 16.5 s). Consistent with previous results obtained for diazepam in humans, alprazolam significantly reduced the amplitude of the startle reflex. A patent increase in onset latency was also observed, this being a novel effect not previously described for benzodiazepines in human studies. Both effects were maximum at 5 h after dosing, the startle response experiencing a recovery as the drug disappeared from systemic circulation. These results indicate a potent inhibitory effect of alprazolam on baseline startle at the dose used, with a robust time-dependent recovery of initial values effectively counteracting between-session habituation. Received: 28 July 1998/Final version: 17 November 1998     

Precipitated withdrawal in squirrel monkeys after repeated daily oral administration of alprazolam,diazepam, flunitrazepam or oxazepam

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam consistently to induce loss of righting reflex in squirrel monkeys or vehicle was orally administered to monkeys on 18 consecutive days: 2 mg/kg alprazolam (n=4), 30 mg/kg diazepam (n=4), 1 mg/kg flunitrazepam (n=4), 280 mg/kg oxazepam (n=5), or vehicle (n=4). Tolerance developed rapidly for loss of righting reflex, more slowly for sleep and only minimally for muscle relaxation observed during the period immediately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg IV) 5 h after the ninth daily oral treatment produced signs of precipitated withdrawal (tremor, vomiting and/or convulsions) in one alprazolam-, four diazepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intravenously several days later under these same experimental conditions failed to provoke a precipitated withdrawal reaction. When flumazenil-induced precipitated withdrawal was again evaluated after the 18th daily oral treatment, withdrawal signs were observed in all alprazolam- and all diazepam-treated monkeys, as well as in three flunitrazepam- and three oxazepam-treated monkeys, but not in the vehicle-treated monkeys (convulsions were observed in one alprazolam-, two diazepam-, one flunitrazepam- and two oxazepam-treated monkeys). No signs of spontaneous withdrawal were observed in any of the monkeys during a subsequent 3-week drug-free period. Thus, repeated administration of approximately equieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occurrence of a precipitated withdrawal reaction).     

坦度螺酮与阿普唑仑治疗广泛性焦虑的对照分析

目的比较坦度螺酮与阿普唑仑治疗广泛性焦虑的临床疗效及不良反应。方法采用随机分组的方法 ,对60例广泛性焦虑患者随机分为坦度螺酮组(30例)和阿普唑仑组(30例),两组疗程均为6周。用焦虑自评量表(SAS)、Hamilton焦虑量表(HAMA)和副反应量表(TESS)评定疗效和不良反应。结果坦度螺酮与阿普唑仑疗效相当,不良反应坦度螺酮组较阿普唑仑组少而轻。结论坦度螺酮治疗广泛性焦虑安全、有效,且不良反应轻微。     

中药新乐康与阿普唑仑治疗失眠对照研究

目的探讨中药新乐康治疗失眠的临床疗效及安全性。方法将53例失眠症患者随机分为中药组31例,对照组22例;中药组给予新乐康治疗,对照组给予阿普唑仑治疗,观察4周。于治疗前及治疗第2周、4周末采用睡眠状态问卷量表评定临床疗效,临床总体量表中对不良反应评分法评定。结果治疗4周末,中药组显效率54.9%,对照组为59.1%（P〉0.05）;SQ评分两组治疗2周末起均较治疗前有极显著性下降（P〈0.01）,并随治疗时间的延续逐渐下降;同期两组间评分差异均无统计学意义（P〉0.05）。中药组的不良反应明显低于阿普唑仑组。结论新乐康治疗失眠疗效与阿普唑仑相当,不良反应明显少于阿普唑仑,安全性、依从性好。     

Effects of single doses of alprazolam and alcohol alone and in combination on psychological performance

The effects of alprazolam l mg alone and in combination with 0·5 g/kg of alcohol for males and 0·42 g/kg for females were examined on a range of psychological tasks 90 and 180 min post-drug (45 and 135 min post-alcohol). Forty-eight healthy volunteers were assigned randomly to four independent groups who received: alprazolam and placebo drink, alprazolam and alcohol, placebo capsule and alcohol, placebo capsule and placebo drink, respectively. Alprazolam caused subjective sedation, unsteadiness, dizziness and physical tiredness and impaired performance on all tasks. Alcohol caused similar subjective effects but little objective impairment. The effects of the combination were generally no greater than predicted from the sum of the single effects.