Comparative anticholinergic activity of oxaprotiline and amitriptyline

As part of a double-blind multicenter trial comparing oxaprotiline with amitriptyline and placebo in 308 outpatients with moderate depression, objective (salivary flow) and subjective (dry mouth, blurred vision/visual disorder, and constipation) determinants of anticholinergic activity were assessed. Both active treatments, but not placebo, induced approximately a 40% reduction in salivary flow after one week of treatment with 75 mg/day h.s. Whereas amitriptyline caused a further reduction (26%) in salivary flow by the end of the trial (week 5), no such reduction was noted with oxaprotiline. With regards to subjective complaints, more patients experienced dry mouth and blurred vision/visual degree of sedation is related to the degree of anticholinergic effects per se. Rather, the sedation may be related to a specific anticholinergic effect, such as changes in salivary flow.     

丙咪嗪和吗氯贝胺疗效预测分析

目的:分析三环类抗抑郁药丙咪嗪和单胺氧化酶抑制剂吗氯贝胺治疗抑郁障碍患者的早期反应是否可以预测药物的远期疗效.方法:采用双盲对照研究方法将200例符合ICD-10抑郁障碍诊断标准的住院或门诊患者,随机分组接受吗氯贝胺(300～600mg·d-1)或丙咪嗪(75～250mg·d-1)治疗6周.并在治疗后第1,2,4,6周末分别进行HAMD,HAMA,CGI和TESS检查,评定药物疗效和安全性.采用相关分析和回归分析,解释治疗第2或4周末疗效对治疗6周末的影响.结果:193例患者完成6周试验.从治疗第1周末开始,2个治疗组HAMD总分均显著下降,并且此后继续下降,两组间比较,减分率均无显著差异.常见的不良反应为胆碱能系统、心血管系统和消化系统反应.从散点图分析,治疗4周末与6周末的HAMD减分率相关性更强,相关系数为0.791(P<0.01),等级相关系数是0.826.但是20%的患者在4～6周期间病情仍在继续改善,治疗4周和6周末HAMD减分率比较,差异有显著性.结论:吗氯贝胺和丙咪嗪治疗2周末的疗效尚不能精确地预测其远期疗效.     

The mechanism of imipramine in enuresis nocturna

1. To evaluate the mechanism of action of imipramine in enuresis nocturna, we compared the effects of imipramine with those of scopolamine butylbromide in fourteen children suffering from this condition. A double-blind, cross-over design was used. 2. Imipramine, 10–20 mg, was superior to scopolamine butylbromide (10–20 mg), in eleven of the fourteen subjects (P< 0.01), and the latter drug was no better than the placebo. 3. As scopolamine butylbromide does not cross the blood-brain barrier, it is concluded that peripheral antimuscarinic effects are not important in the beneficial effects of imipramine in enuresis nocturna. 4. The therapeutic effects of imipramine in depression frequently take 3 to 4 weeks to develop. Such a delay was not seen in our enuretic patients. Thus the mechanism of the drug in the two conditions is probably different.     

Mianserin and trazodone for cardiac patients with depression

Summary In a placebo controlled double-blind cross-over study, the cardiovascular and antidepressant effects of three weeks' treatment with mianserin (30–80 mg daily) and trazodone (150–400 mg daily) were studied in depressed patients who had co-existant cardiac disease.In 14 of the 16 patients, no haemodynamic deterioration occurred with either drug. Two patients withdrew from the study. One with coronary artery disease, whose concomitant medication included a calcium-antagonist and a beta-adrenoceptor blocker and who developed severe postural hypotension after his first dose of trazodone while the other had an increased frequency of transient cerebral ischaemic attacks with both mianserin and trazodone, but not with placebo.Mianserin and trazodone are comparable for both antidepressant efficacy and paucity of cardiovascular effects. Although unwanted effects were generally mild, the incidence of dizziness was greater in those patients receiving trazodone. Caution is advised, however, when prescribing either drug to patients with transient cerebral ischaemic attacks or those with coronary artery disease receiving medication.     

Drugs with anticholinergic properties: a current perspective on use and safety

Introduction: Many commonly used drugs have primary or secondary anticholinergic effects contributing to adverse outcomes ranging from mild-to-severe to potentially lethal. Anticholinergic adverse effects frequently occur with medications prescribed with other intended mechanisms of action, including antihistamines, antidepressants, and antipsychotics. Anticholinergic drugs are also the principal treatments of clinical conditions, such as urinary incontinence, that tend to occur in the elderly. Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment.

Areas covered: Medline and Pubmed literature searches (1966 – the present) were performed using ‘anticholinergic’ and ‘drug safety’. Abstracts were assessed and references scanned for appropriate articles. Here, the authors i) describe the neural pathways of the cholinergic system; ii) outline the main clinical uses and adverse effects of anticholinergic agents with a focus on cognitive impairment; and iii) discuss anticholinergic safety monitoring.

Expert opinion: Prescribers need to be vigilant for adverse anticholinergic effects, particularly in older patients. The symptoms may range from subtle cognitive impairment to delirium and may be due to the cumulative effect of multiple medications of modest antimuscarinic activity. The Anticholinergic Drug Scale and tables listing drugs with known anticholinergic properties may help in guiding clinical decision-making to reduce anticholinergic burden.     

The effects of imipramine and iprindole on the metabolism of octopamine in the rat

Acute injections of imipramine and iprindole in rats produced significant decreases in the concentration of p-hydroxyphenylglycol (pHPG), a neutral metabolite of octopamine in brain at 6 and 24 hr after the administration of drugs. The 24-hr urinary levels of both free and total pHPG were reduced to 25-29% of control with acute administration of imipramine, while iprindole produced a 30% decrease in free pHPG. With chronic administration of imipramine, concentrations of pHPG in brain returned to normal, while the 24-hr urinary levels were still decreased (to 24%). Octopamine in brain was unaltered after both single and repeated injections of imipramine. Thus, these data suggest that the turnover of octopamine in brain is reduced after acute administration of imipramine and iprindole, while after chronic treatment with imipramine, turnover of octopamine in brain has returned to control levels.     

曲唑酮治疗抑郁症睡眠障碍病人多导睡眠图变化

目的:探讨抑郁症合并睡眠障碍病人多导睡眠图特点,并与正常人比较,探讨曲唑酮治疗效果及多导睡眠图(PSG)变化。方法:应用Polysmith型多导睡眠图,对21名抑郁症合并睡眠障碍病人及10名正常对照者进行测定,抑郁症病人曲唑酮治疗2mo后复查多导睡眠图,并进行治疗前后抑郁自评量表、汉密尔顿焦虑量表测定。测量数据以(?)±s表示,统计方法采用SPSS 11.0进行分析。结果:与正常对照者比较,抑郁症合并睡眠障碍病人觉醒时间、快动眼(REM)睡眠、S2显著延长,总睡眠时间、睡眠效率、REM睡眠潜伏期、慢波(S3+S4)睡眠明显缩短。抑郁症组曲唑酮治疗后PSG显示总睡眠时间延长[治疗前(350±s 30)min,治疗后(393±27)min,P<0.01],睡眠效率增加[治疗前(74.0±2.0)%,治疗后(86±4)%,P<0.05],觉醒时间缩短[治疗前(82±7)min,治疗后(19±5)min,P<0.01],REM睡眠缩短[治疗前(107±13)min,治疗后(98±7)min,P<0.01],S2缩短[治疗前(189±5) min,治疗后(181±4)min,P<0.05],慢波睡眠延长[治疗前(40±3)min,治疗后(69.0±2.0) min,P<0.01]。睡眠潜伏期、REM睡眠潜伏期、REM睡眠次数、S1未见明显变化(P>0.05)。抑郁自评量表和汉密尔顿焦虑量表评分改善。结论:抑郁症合并睡眠障碍病人PSG指标异常,曲唑酮治疗后睡眠好转,精神量表及PSG异常指标有改善。     

Pre- and postsynaptic α-adrenergic receptor effects of trazodone in the anesthetized dog

The α-adrenergic blocking properties of trazodone were assessed in spinal-sectioned, vagotomized dogs. Both the inhibition by clonidine of the tachycardia produced by continuous cardiac accelerator nerve stimulation (presynaptic effect) and the vasopressor effects of clonidine (postsynaptic effect) were antagonized by trazodone and phentolamine in this model. The results indicate that although it is 12–18 times less potent on a weight basis, trazodone, like phentolamine, blocks presynaptic α-adrenergic receptors on the cardiac nerves of anesthetized dogs. Trazodone, unlike imipramine, did not potentiate the positive inotropic responses elicited by exogenously administered norepinephrine. The latter observation supports the interpretation that trazodone altered positive chronotropic responses to cardiac accelerator nerve stimulation via presynaptic α-receptor blockade rather than by either an interference with neuronal reuptake of norepinephrine or a heightening of ß-adrenergic receptor sensitivity.     

Comparison of imipramine-imipraminium in mice. To elucidate central or peripheral origin of effects of imipramine

Imipramine hydrochloride shows effects in a battery of tests used for the screening of antidepressant drugs. The central origin of these pharmacological effects of imipramine has not been clearly established. Imipramine methiodide is a quaternary derivative of imipramine which does not cross the blood-brain barrier easily. The effects of the two forms of imipramine have been compared: on an effect known to have a central origin; on two effects known to have a peripheral origin; on a battery of tests used for the screening of antidepressant drugs. It has been demonstrated that imipramine methiodide is as active as imipramine hydrochloride on two effects of peripheral origin, less active than imipramine hydrochloride on an effect considered to have a central origin and less active than imipramine hydrochloride or inactive on the tests which are used for the screening of antidepressant drugs. Consequently, the tests used for the screening of antidepressant drugs represent, primarily or exclusively, effects of central origin.     

HPLC法测定人血浆中曲唑酮的浓度

目的 :建立测定人血浆中曲唑酮 (TZD)浓度的RP HPLC法。方法 :以美国Dikma公司DiamonsilTMC18反相柱 (2 5 0mm×4 6mm ,5 μm)为色谱柱 ,流动相为甲醇 超纯水 (85∶15 ,V/V) ,流速为 0 8mL·min-1,检测波长 2 5 6nm ,以乙酸乙酯为提取剂。结果 :TZD高 (83 33mg·L-1)、中 (16 6 7mg·L-1)、低 (1 6 7mg·L-1) 3个浓度的平均回收率分别为 10 0 19% ,97 4 5 % ,95 5 1% ;日内、日间RSD均 <5 % (n =5 ) ;分析方法的最低检测浓度为 0 0 8mg·L-1。线性范围为 0 83～ 16 6 6 7mg·L-1,回归方程为Y =0 0 2 16X - 0 0 0 333,r=0 9999(n =10 )。结论 :该方法可用于临床TZD血药浓度监测和药动学研究     

Some effects of imipramine on micturition and their relevance to its anti-enuretic activity.

Voiding was induced in conscious cats by an infusion of saline into the bladder via a chronically implanted catheter. Imipramine (1 mg/kg), a dose equivalent to 25 mg for a 7 year old child, increased the functional bladder capacity by maxima of between 35 and 160%. an effect lasting some 15hr. The effect was not due to the local anaesthetic, muscle depressant or cholinolytic activities of imipramine. Imipramine potentiated detrusor relaxation evoked by hypogastric nerve stimulation in anaesthetized cats, an effect explained by inhibition of noradrenaline reuptake. Since the role of the hypogastric innervation in micturition is as yet incompletely understood, it is not possible to state whether the anti-enuretic activity of imipramine can be attributed to this action or whether an effect at the central level is more important.     

Double-blind placebo-controlled study of the autonomic effects of clovoxamine,imipramine, and amitriptyline in normal volunteers

The autonomic effects of clovoxamine, a possible new antidepressant, were compared with placebo, imipramine, and amitriptyline in a double-blind, repeated-measures, latin-square study design, using 16 healthy volunteers. Salivary flow, pupillary response, near-point accommodation, and pilocarpine-evoked miosis were assessed before and 1, 2, and 3 hours after each treatment condition. Dose-related autonomic effects were seen with all three active drugs. Clovoxamine at a 50-mg dose was not distinguishable from placebo. For salivary flow, perhaps the most reliable index of anticholinergic activity, the effects of 100-mg and 150-mg doses of clovoxamine were comparable to those of 50-mg and 75-mg doses of imipramine but were less than those of 50- and 75-mg doses of amitriptyline at 3 hours postdosing.     

曲唑酮与帕罗西汀治疗焦虑症病人睡眠障碍的比较

目的 :比较曲唑酮和帕罗西汀对焦虑症病人睡眠障碍的疗效。方法 :4 5例焦虑症病人随机分为 2组。曲唑酮组 2 2例 ,给予曲唑酮 5 0～ 10 0mg·d- 1,qn× 8wk。帕罗西汀组 2 3例 ,给予帕罗西汀2 0～ 4 0mg·d- 1,qn× 8wk。结果 :睡眠障碍因子评分 :在 1wk时 ,曲唑酮组 3.0±s 1.7,帕罗西汀组4 .0± 1.6 ;在 2wk时 ,曲唑酮组 1.3± 1.2 ,帕罗西汀组 2 .3± 1.3(均P <0 .0 5 )。总睡眠时间 :2组比较在 1wk时差异有非常显著意义 (P <0 .0 1) ;在 2wk时差异有显著意义 (P <0 .0 5 )。早醒现象 :2组比较在 2 ,4wk时差异均有显著意义 (P <0 .0 5 )。睡眠增多、嗜睡不良反应分别为 0 / 2 3,6 / 2 2 (P <0 .0 5 )。结论 :曲唑酮比帕罗西汀改善睡眠见效早、作用快、作用强 ,睡眠时间长 ,早醒现象轻     

Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII–R primary insomnia

Trazodone is an antidepressant which is used at low doses as a hypnotic. The hypnotic efficacy of trazodone in non-depressed insomniacs is unknown, especially in comparison to hypnotic medications such as zolpidem. Following a placebo screening week, DSM-IIIR defined primary insomniacs were randomized into a parallel-group, double-blind, 14-day comparison of trazodone 50 mg, zolpidem 10 mg and placebo. Patients completed daily morning questionnaires and weekly office visits. Self-reported sleep latencies were compared by the Cox proportional hazards regression technique; self-reported sleep duration by ANOVA. During treatment Week 1, both drugs produced significantly shorter self-reported sleep latencies and longer self-reported sleep durations than placebo. Self-reported sleep latency was significantly shorter with zolpidem than with trazodone. During Week 2, only the zolpidem group maintained a significantly shorter sleep latency than the placebo group, and self-reported sleep duration did not vary significantly among groups. The incidence of adverse events was low in all groups. Both trazodone and zolpidem improved self-reported sleep latency and duration of non-depressed, primary insomniacs; zolpidem was somewhat more efficacious at the doses studied. © 1998 John Wiley & Sons, Ltd.     

Drugs with anticholinergic effects and cognitive impairment,falls and all-cause mortality in older adults: A systematic review and meta-analysis

AimThe aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults.MethodsA literature search using CINAHL, Cochrane Library, Embase and PubMed databases was conducted for randomized controlled trials, prospective and retrospective cohort and case-control studies examining the use of DACEs in subjects ≥65 years with outcomes on falls, cognitive impairment and all-cause mortality. Retrieved articles were published on or before June 2013. Anticholinergic exposure was investigated using drug class, DACE scoring systems (anticholinergic cognitive burden scale, ACB; anticholinergic drug scale, ADS; anticholinergic risk scale, ARS; anticholinergic component of the drug burden index, DBI_AC) or assessment of individual DACEs. Meta-analyses were performed to pool the results from individual studies.ResultsEighteen studies fulfilled the inclusion criteria (total 124 286 participants). Exposure to DACEs as a class was associated with increased odds of cognitive impairment (OR 1.45, 95% CI 1.16, 1.73). Olanzapine and trazodone were associated with increased odds and risk of falls (OR 2.16, 95% CI 1.05, 4.44; RR 1.79, 95% CI 1.60, 1.97, respectively), but amitriptyline, paroxetine and risperidone were not (RR 1.73, 95% CI 0.81, 2.65; RR 1.80, 95% CI 0.81, 2.79; RR 1.39, 95% CI 0.59, 3.26, respectively). A unit increase in the ACB scale was associated with a doubling in odds of all-cause mortality (OR 2.06, 95% CI 1.82, 2.33) but there were no associations with the DBI_AC (OR 0.88, 95% CI 0.55, 1.42) or the ARS (OR 3.56, 95% CI 0.29, 43.27).ConclusionsCertain individual DACEs or increased overall DACE exposure may increase the risks of cognitive impairment, falls and all-cause mortality in older adults.     

Echocardiographic and psychometric effects of amitriptyline or imipramine plus alcohol

Summary The echocardiographic and psychometric effects of amitriptyline or imipramine combined with alcohol have been studied in a double-blind cross-over trial in 7 healthy volunteers. Amitriptyline or imipramine 25 mg b.d. were given for three days and then the dose was doubled. On Days 1 and 10–13 echocardiographic measurements were done, and on Day 15 psychomotor tests were performed. Ethanol 1 g/kg in each session was administered 1 h after drug intake.Alcohol alone increased heart rate and decreased the systolic blood pressure and ejection fraction. It also impaired most of the psychomotor measures, horizontal nystagmus being the most sensitive test.On Day 1, the first dose of imipramine decreased the heart rate and increased diastolic blood pressure. These effects were partly counteracted by alcohol. Imipramine + alcohol decreased the WSTR. Amitriptyline alone did not affect the echocardiographic findings on Day 1. In combination with alcohol it reduced cardiac output and prolonged PEP, and increased the PEP/LVET ratio.During subacute treatment (Days 10–13) WSTR was increased by both antidepressants, but only amitriptyline increased the heart rate. Unlike imipramine + alcohol, amitriptyline + alcohol decreased WSTR and MCSR.Digit symbol substitution was the only psychometric test in which the alcohol effect was clearly enhanced by both amitriptyline and imipramine.     

Effects of imipramine,bupropion, chlorpromazine,and clozapine on differential-reinforcement-of-low-rate (DRL) > 72-Sec and > 36-sec schedules in rat

The hypothesis that a DRL schedule requiring a long pause (> 72 sec) specifically identifies antidepressant drugs was evaluated in rats pressing a lever for food reinforcement. The tricyclic antidepressant imipramine decreased responses and increased reinforcements as previously shown. However, the antipsychotics chlorpromazine and clozapine had a similar effect, as did prefeeding, and the atypical antidepressant bupropion increased responses and decreased reinforcements. Because mean baseline reinforcement rate was lower than in previous studies showing drug class specificity, the DRL requirement was reduced to > 36 sec and the drugs were tested again; effects were qualitatively similar to those in DRL > 72 in the first part of the study. The results suggest that a drug-induced reduction in responses could account for the increase in reinforcements, that if drug class specificity exists it may occur only when baseline response and reinforcement rates are confined to a narrow range, that the failure of previous studies to show antidepressant type effects with nonantidepressants could have resulted from choice of drugs and doses, and that the type of reinforcer could be an important factor.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.