Seizures due to maprotiline overdose

Maprotiline, a new tetracyclic antidepressant, has a pattern of toxicity that is different from that of tricyclics. Maprotiline overdosage appears more likely to cause seizures but less likely to cause the peripheral autonomic and cardiac manifestations seen with tricyclics. Two cases of maprotiline overdose resulting in seizures without significant anticholinergic or cardiotoxic effects are presented. Both patients were treated acutely with gastric emptying and were observed to have no further seizures during subsequent drug-free hospital and outpatient follow up. Physostigmine salicylate has been used as an antidote for the anticholinergic syndrome of tricyclic overdose, but probably offers less in maprotiline overdose. Careful observation for seizures appears to be warranted.     

Overdosage of antidepressants: Clinical and pharmacokinetic aspects

Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (>500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.     

丹栀逍遥散治疗抑郁症的临床疗效观察

目的 观察丹栀逍遥散治疗抑郁症的临床疗效及不良反应。方法 采用随机双盲对照方法,将63例患者分为两组,分别用麦普替林（西药组3l例）和丹栀逍遥散（中药组32例）治疗,于用药前及用药2、4、6周时采用汉米尔顿抑郁量表（HAMD）、抑郁自评量表（SDS）、焦虑自评量表（SAS）及中医症状辨证量表等评定药物疗效,用Asberg副反应量表评定不良反应。结果 两组临床疗效比较差异无显著性;两组治疗后HAMD、SDS和SAS积分均明显低于治疗前（P〈0．05）,但两组间比较差异无显著性;中医症状辨证量表评定两组间差异无显著性;Asberg副反应量表分值中药组低于西药组（P〈0．05）。结论 丹栀逍遥散治疗抑郁症疗效与麦普替林相当,而不良反应明显少于麦普替林。     

Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist

Background and purpose:

Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being Δ⁹-tetrahydrocannabinol, cannabidiol and Δ⁹-tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor.

Experimental approach:

The [³⁵S]GTPγS binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [³H]CP55940 from mouse CB₁ and human CB₂ cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.

Key results:

In the brain membrane experiments, cannabigerol behaved as a potent α₂-adrenoceptor agonist (EC₅₀= 0.2 nM) and antagonized the 5-HT_1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K_B= 51.9 nM). At 10 µM, it also behaved as a CB₁ receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be α₂-adrenoceptor-mediated (EC₅₀= 72.8 nM) and displayed significant affinity for mouse CB₁ and human CB₂ receptors.

Conclusions and implications:

This investigation has provided the first evidence that cannabigerol can activate α₂-adrenoceptors, bind to cannabinoid CB₁ and CB₂ receptors and block CB₁ and 5-HT_1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [³⁵S]GTPγS binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain.     

西酞普兰与麦普替林治疗老年抑郁症对照研究

目的 探讨西酞普兰与麦普替林治疗老年抑郁症的临床疗效及安全性.方法 将66例老年抑郁症患者随机分为两组各33例,研究组给予西酞普兰治疗,对照组给予麦普替林治疗,疗程6w.采用汉密顿抑郁量表评定临床疗效,副反应量表评定不良反应.结果 两组治疗1 w、2 w末汉密顿抑郁量表评分均较治疗前显著下降(P＜0.05或0.01),研究组较对照组下降显著(P＜0.01或0.05);治疗6 w末研究组显效率81.8%,总有效率93.9%;对照组分别为75.8%,87.9%.两组总体疗效相当(P＞0.05),但研究组不良反应较对照组发生率低,且程度轻,差异有显著性(P＜0.05).结论 西酞普兰治疗老年抑郁症起效快,疗效显著,安全性高,依从性好.     

Double-blind comparison between a serotonin and a noradrenaline reuptake blocker in the treatment of depressed outpatients. Clinical aspects

Seventy-five outpatients with major depressive disorder (RDC) were randomly referred to treatment with a dominant serotonin (5-HT) uptake inhibiting drug (zimeldine, 100 mg b.i.d.) or a dominant noradrenaline (NA) uptake inhibiting drug, (maprotiline, 75 mg b.i.d.). The total antidepressive effect was similar in the two groups for up to 4 weeks of treatment. Both drugs gave an effect on the depressive syndrome as a whole, with no preference for mood, anxiety, retardation or vital symptoms. Good response to the NA drug correlated to few prior episodes and few years since first episode, whereas the 5-HT drug had its best effect when there were several previous episodes.     

Interaction of alcohol with maprotiline or nomifensine: Echocardiographic and psychometric effects

Summary Eight healthy volunteers received low doses of maprotiline and nomifensine up to 50 mg b. d. for 15 days in a double-blind, cross-over, placebo controlled study, during which echocardiography and psychomotor testing were carried out before and after the intake of alcohol 1 g/kg.Maprotiline increased heart rate and cardiac output and reduced peripheral resistance compared to placebo and nomifensine. Nomifensine alone was associated with a slight decrease in heart rate. Alcohol alone caused a significant increase in diastolic blood pressure, but did not otherwise modify the cardiovascular measures. The antidepressants did not augment the effects of alcohol.Antidepressants alone had no effect on psychomotor skills, but alcohol always impaired performance. No additional effects of alcohol were produced by the antidepressants.It appears that practically important peripheral or central consequences are unlikely to follow drinking a moderate amount of alcohol during regular therapy with low therapeutic doses of catecholamine reuptake inhibiting antidepressants. Experimental studies of the interaction of antidepressants and alcohol in patients with chronic heart disease seem to be justified.     

Effect of the antidepressant maprotiline on Ca2+ movement and proliferation in human prostate cancer cells

1. The effect of maprotiline, an antidepressant, on human prostate cells is unclear. In the present study, the effect of maprotiline on [Ca2+]i and growth in PC3 human prostate cancer cells was measured using the fluorescent dyes fura-2 and tetrazolium, respectively. 2. Maprotiline caused a rapid, concentration-dependent increase in [Ca2+]i (EC50 = 200 micromol/L). The maprotiline-induced [Ca2+]i increase was reduced by removal of extracellular Ca2+ or pretreatment with nicardipine. 3. The maprotiline-induced Mn2+ influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca2+ influx. 4. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca2+]i increase, after which the effects of maprotiline of increasing [Ca2+]i were abolished. In addition, pretreatment with maprotiline reduced a major portion of the thapsigargin-induced increase in [Ca2+]i. 5. U73122, an inhibitor of phospholipase C, abolished the ATP (but not maprotiline)-induced increase in [Ca2+]i. 6. Overnight incubation with 1-10 micromol/L maprotiline did not alter cell proliferation, although incubation with 30-50 micromol/L maprotiline decreased cell proliferation. 7, These findings suggest that maprotiline rapidly increases [Ca2+]i in human prostate cancer cells by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release and that it may modulate cell proliferation in a concentration-dependent manner.     

马普替林与阿米替林治疗抑郁症对比

报道国产马普替林（男性２１例，女性７例；年龄３７±ｓ１３ａ）与阿米替林（男性１９例，女性９例；年龄３８±１１ａ）治疗５６例抑郁症的对照实验。开始剂量均为５０ｍｇ／ｄ，ｌｗｋ内加至１５０－２５０ｍｇ／ｄ，共４ｗｋ。结果显示：２个药抗抑郁疗效相仿，ＨＡＭＤ总分的减分，差别无显著意义（Ｐ＞０．０５）。２个药主要不良反应为口干、便秘、头晕、视物模糊等抗胆碱能症状。