Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers

Frodl T, Stauber J, Schaaff N, Koutsouleris N, Scheuerecker J, Ewers M, Omerovic M, Opgen‐Rhein M, Hampel H, Reiser M, Möller H.‐J, Meisenzahl E. Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers. Objective: Results in adult attention deficit hyperactivity disorder (ADHD) on structural brain changes and the clinical relevance are contradictory. The aim of this study was to investigate whether in adult patients with ADHD hippocampal or amygdala volumes differs from that in healthy controls and patients with major depression (MD). Method: Twenty patients with ADHD, 20 matched patients with MD and 20 healthy controls were studied with high resolution magnetic resonance imaging. Results: Amygdala volumes in patients with ADHD were bilaterally smaller than in patients with MD and healthy controls. In ADHD, more hyperactivity and less inattention were associated with smaller right amygdala volumes, and more symptoms of depression with larger amygdala volumes. Conclusion: This study supports findings that the amygdala plays an important role in the systemic brain pathophysiology of ADHD. Whether patients with ADHD and larger amygdala volumes are more vulnerable to affective disorders needs further investigation.     

A low molecular weight heparin compared with unfractionated heparin

A 6000 daltons low molecular weight heparin (LMWH) was compared with unfractionated mucosal heparin in vitro and in vivo. Despite unimpressive specifications by clotting assays in vitro, the LMWH gave high and sustained activity in vivo by anti-Factor Xa assays, following subcutaneous injection. However, activity measured by APTT and calcium thrombin time assays was at least as high as occurred following unfractionated heparin. On the basis of clotting assays, there seems no reason to expect a lower incidence of haemorrhagic side-effects following the clinical use of this LMWH. The study also strikingly demonstrates the inadequacy of in vitro clotting assays for assessing the in vivo behaviour of LMWH.     

Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers

OBJECTIVE: Increased circulating levels of hemostatic factors have been associated with arterial and venous thrombosis. Although in vitro evidence suggests that glucocorticoids may activate hemostasis and inhibit thrombolysis, no controlled in vivo studies have examined the effects of glucocorticoids on hemostatic factors. We hypothesized that a 5-day treatment course of dexamethasone would increase circulating levels of hemostatic and anti-fibrinolytic factors. METHODS: We randomized 24 healthy men ages 19-39 to receive either dexamethasone 3 mg twice daily versus placebo for 5 days. Parameters examined before and after the intervention included: clotting factors VII, VIII, and XI, von Willebrand factor (vWF), D-dimer, PAI-1, soluble CD40-ligand (sCD40-ligand), and fibrinogen. RESULTS: Dexamethasone tended to modestly increase clotting factors levels and fibrinogen without significantly affecting PAI-1, D-dimer or sCD40-ligand. Factor VII increased by a mean of 13% (p = 0.04 versus placebo), factor VIII by 27% (p = 0.0008), factor XI by 6% (p = 0.01), and fibrinogen by 13% (p = 0.05). CONCLUSIONS: Glucocorticoids may increase the activity of clotting factors in vivo. This may contribute to the reported increased risk of thrombosis in patients with sustained exposure to glucocorticoids.     

Liquoid,a weak anticoagulant with strong “procoagulant” properties as compared with heparin

The influence of the synthetic acid polymer Liquoid and of heparin on precipitation of fibrinogen, clotting of fibrinogen by thrombin and on platelet aggregation was studied.In contrast to heparin, Liquoid was a potent precipitant of fibrinogen.The weak anticoagulant effect of Liquoid was restricted to the enzymatic phase and was not influenced by antithrombin III (heparin cofactor). Actually, Liquoid inhibited antithrombin III.Liquoid and heparin induced platelet aggregation, most likely by identical mechanisms, but Liquoid was by far more potent than heparin. Heparin markedly inhibited thrombin-induced platelet aggregation, mainly through its effect on antithrombin III. No inhibition by Liquoid was observed, probably due to aggregation induced by Liquoid itself.     

Enhanced antiplatelet effects of clopidogrel plus acetylsalicylic acid compared with acetylsalicylic acid alone or combined with extended-release dipyridamole in healthy volunteers

BACKGROUND: Previous studies have shown the potential benefit of using antiplatelet agents with complementary modes of action. METHODS: Using a crossover design, the ex vivo antiplatelet effects of 10 days' treatment with clopidogrel 75 mg + acetylsalicylic acid (ASA) 75 mg daily, ASA 75 mg/day, or extended-release dipyridamole 200 mg/low-dose ASA 25 mg twice daily were compared, using various platelet agonists. RESULTS: Clopidogrel + ASA was significantly more effective than dipyridamole + ASA in inhibiting collagen-induced platelet aggregation in whole blood (mean 44.9 +/- 5.6% inhibition vs. 16.5 +/- 6.7%; p = 0.0009). Clopidogrel + ASA was significantly more effective than ASA or dipyridamole + ASA in inhibiting ADP-induced platelet aggregation in whole blood (p < or = 0.0001) and platelet-rich plasma (PRP) (p < or = 0.0001), and in inhibiting collagen-induced aggregation in PRP (p < or = 0.0001). ASA alone and clopidogrel + ASA were significantly more effective than dipyridamole + ASA in inhibiting arachidonic acid-induced platelet aggregation in whole blood (p < or = 0.0001). CONCLUSIONS: Based on ex vivo platelet aggregometry, clopidogrel + ASA is a more potent antiplatelet regimen than either ASA alone or the marketed combination of dipyridamole + ASA. However, the clinical significance of this finding remains to be confirmed.     

Pharmacokinetic and pharmacodynamic characteristics of a controlled-release formulation of trazodone versus the conventional formulation in healthy volunteers

The pharmacokinetic and pharmacodynamic characteristics of a controlled-release (CR) formulation of trazodone were evaluated in healthy subjects who received acutely 150 mg and 75 mg of the CR trazodone and equal amounts of the conventional formulation on separate occasions. Plasma trazodone concentrations were measured by HPLC. The pharmacokinetic profile of CR trazodone was characterized by a slower increase in drug plasma levels and a lower and retarded peak plasma concentration without any modification in the total amount of trazodone absorbed over 24 hrs. The side effects were less severe and less frequent than with the conventional formulation.

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Sommario Le caratteristiche farmacocinetiche e farmacodinamiche di una formulazione di trazodone a rilascio controllato (CR) sono state studiate in volontari sani ai quali furono somministrati, in quattro differenti occasioni, 150 mg e 75 mg di trazodone CR e dosi equivalenti di trazodone in formulazione convenzionale. Le concentrazioni plasmatiche di trazodone furono misurate mediante HPLC. Rispetto alla formulazione convenzionale, il trazodone CR esibì un profilo farmacocinetico caratterizzato da un incremento più graduale dei livelli plasmatici e da una concentrazione massima più bassa e più ritar-data. Nessuna differenza nella quantità totale di farmaco assorbita nelle 24 ore fu osservata tra le due formulazioni. Dopo somministrazione del trazodone CR, gli effetti collaterali indesiderati furono meno severi e meno frequenti rispetto alla formulazione convenzionale.

     

Superior efficacy of clopidogrel plus acetylsalicylic acid compared with extended-release dipyridamole plus acetylsalicylic acid in preventing arterial thrombogenesis in healthy volunteers

INTRODUCTION: Recent ex vivo platelet aggregometry data indicate that clopidogrel 75 mg/day plus acetylsalicylic acid (ASA) 75 mg/day is a more potent antiplatelet regimen than the marketed combination of dipyridamole+ASA. The present study was designed to assess the antithrombotic effect of both dual antiplatelet regimens using a human ex vivo model of arterial thrombosis. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. During two 10-day treatment periods separated by a 14-day washout period, 23 healthy male volunteers received once-daily clopidogrel 75 mg plus acetylsalicylic acid 75 mg, or twice-daily extended-release dipyridamole 200 mg plus acetylsalicylic acid 25 mg. Assessments were made at baseline and on Day 10 of each period. Arterial thrombus formation was induced ex vivo by exposing a collagen-coated surface in a parallel-plate perfusion chamber to native blood for 3 min (arterial wall shear rate 2600 s(-1)). Total platelet and fibrin deposition was determined by immunoenzymatic methods. RESULTS: Compared with baseline values, the mean inhibition of total platelet deposition was 63.9+/-5.9% with clopidogrel plus acetylsalicylic acid, compared with 18.4+/-5.6% for extended-release dipyridamole plus acetylsalicylic acid (67% reduction; 95% CI, 49-79%; p<0.0001). Corresponding figures for fibrin deposition were 64.9+/-4.8% and 18.3+/-9.7%, respectively (58% reduction; 95% CI, 45-67%; p<0.0001). Both treatments were well tolerated. CONCLUSIONS: Clopidogrel plus acetylsalicylic acid showed significantly superior antithrombotic efficacy compared with extended-release dipyridamole plus acetylsalicylic acid in preventing arterial thrombogenesis in humans.     

睡眠剥夺对健康青年男性工作记忆的影响及莫达非尼的干预作用

目的 探讨不同时间睡眠剥夺对健康青年男性工作记忆的影响,以及莫达非尼对睡眠剥夺的对抗作用. 方法 10名健康男性青年志愿者进行间隔1周的3次36 h睡眠剥夺,第一次不服药,为剥夺组,后2次志愿者交叉服用莫达非尼和安慰剂(于睡眠剥夺14 h和24h 2次服用1.每次服药后3 h进行工作记忆任务测试(倒数n项测验),剥夺组也在同样的时间进行测试.把睡眠剥夺前清醒时设为正常对照组.并进行测试. 结果 剥夺组的1-back任务的第2次测试平均反应时间较第1次测试明显延长,2-back任务的第2次测试平均反应时间、错误率较第1次测试明显增高,差异均有统计学意义(P＜0.05).剥夺组的l-back任务的第2次测试错误率与平均反应时间均比正常对照组明显增高,2-back任务的两次测试平均反应时间和错误率较正常对照组明显增高,差异均有统计学意义(P＜0.05).莫达非尼组的1-back任务的第2次测试平均反应时间较剥夺组明显降低,2-back任务的两次测试平均反应时间和错误率较剥夺组明显降低,差异均有统计学意义(P＜0.05). 结论 睡眠剥夺后工作记忆受到损害,并随着剥夺时间延长,受损加重.莫达非尼对睡眠剥夺后的工作记忆损害有明显的改善作用.     

Effects of acute tryptophan depletion on executive function in healthy male volunteers

Background  

Neurocognitive impairment is frequently described in a number of psychiatric disorders and may be a direct consequence of serotonergic dysfunction. As impairments in executive functions are some of the most frequently described, the purpose of this study was to examine the performance of normal volunteers on a range of executive tasks following a transient reduction of central serotonin (5-HT) levels using the method of acute tryptophan depletion (ATD).     

Effects of levetiracetam on nocturnal sleep and daytime vigilance in healthy volunteers

PURPOSE: Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity or antiepileptic drugs (AEDs) or both. To study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after 3 weeks of treatment. METHODS: The study was of a double-blind crossover design with random allocation of multiple doses of two different treatments (randomly first LEV 相似文献   

Effects of different sleep deprivation protocols on sleep perception in healthy volunteers

Objectives

To investigate whether different protocols of sleep deprivation modify sleep perception.

Methods

The effects of total sleep deprivation (TD) and selective rapid eye movement (REM) sleep deprivation (RD) on sleep perception were analyzed in normal volunteers. Thirty-one healthy males with normal sleep were randomized to one of three conditions: (i) normal uninterrupted sleep; (ii) four nights of RD; or (iii) two nights of TD. Morning perception of total sleep time was evaluated for each condition. Sleep perception was estimated using total sleep time (in hours) as perceived by the volunteer divided by the total sleep time (in hours) measured by polysomnography (PSG). The final value of this calculation was defined as the perception index (PI).

Results

There were no significant differences among the three groups of volunteers in the total sleep time measured by PSG or in the perception of total sleep time at baseline condition. Volunteers submitted to RD exhibited lower sleep PI scores as compared with controls during the sleep deprivation period (P < 0.05). Both RD and TD groups showed PI similar to controls during the recovery period.

Conclusion

Selective REM sleep deprivation reduced the ability of healthy young volunteers to perceive their total sleep time when compared with time measured by PSG. The data reinforce the influence of sleep deprivation on sleep perception.     

Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.     

Cavum septum pellucidum in subjects at ultra-high risk for psychosis: compared with first-degree relatives of patients with schizophrenia and healthy volunteers

OBJECTIVE: The cavum septum pellucidum (CSP) is a space between the two leaflets of the septum pellucidum, and is a putative marker of disturbance in early brain development. We examined whether CSP was present more frequently in subjects at ultra-high risk (UHR) for psychosis compared to first-degree relatives of patients with schizophrenia (genetic high risk, GHR) and healthy controls (HC). METHODS: We evaluated CSP in 87 subjects (30 UHR, 23 GHR, and 34 HC) according to a published grading system using high-resolution magnetic resonance imaging (MRI) with 0.45-mm slice thickness. We also assessed two other criteria: presence of CSP on at least one MRI slice, and abnormally large CSP (i.e., > or =6 mm in length). Correlational analysis between CSP measures and clinical symptoms was also examined. RESULTS: Based on the grading scale, the UHR group exhibited a significantly higher incidence of abnormal CSP (grades 2, 3, and 4) compared to the HC group, but there were no significant differences in the incidence of abnormal CSP between the UHR and GHR or the GHR and HC groups. There were no significant differences among the groups in the presence of CSP on at least one MRI slice or abnormally large CSP based on the length of CSP. In addition, no significant correlations between CSP measures and clinical symptoms were found. CONCLUSION: These findings suggest that abnormal CSP might be associated with susceptibility to psychosis, although the CSP itself might be a normal anatomical variant. Further studies using a larger sample are needed to clarify issues on neurodevelopmental perspective in subjects at high risk for psychosis.     

Background factors in patients with schizoaffective disorder as compared with patients with diabetes and healthy individuals

Family history and psychosocial background factors were studied in married patients with a DSM-III diagnosis of schizoaffective disorder (n=17, partnersn=16), married patients with diabetes (n=10, partnersn=10) and married healthy individuals (n=8, partnersn=8). The two latter groups were comparison control groups matched for gender and age to the patients with schizoaffective disorder. Affective disorder, not particularly schizoaffective disorder, was more common in first- and tended to be more common in second-degree relatives of patients with schizoaffective disorder as compared with controls. Poor parental relations, especially to the father, during the formative years were prominent in patients with schizoaffective disorder as compared with the controls. The same patients also more often than others gave a report of sexual enroachment, inside or outside the family, and corporal punishment during the growing-up years.     

Oxcarbazepine does not interact with cimetidine in healthy volunteers

When cimetidine (CIM) is administered together with the anti-epileptic drug carbamazepine (CBZ), a drug interaction may cause a rise in plasma concentrations of CBZ, which can result in CBZ-related toxic symptoms. The aim of this cross-over study was to investigate whether CIM influences the disposition and kinetics of the new anti-epileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there was no difference in AUC, Cmax or tmax when OXC was administered either with or without CIM. The results of this study suggest that in the treatment of epilepsy OXC offers an important advantage over the established anti-epileptics, especially when concomitant therapy with CIM is required.     

Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers

Ketorolac is a potent cyclo-oxygenase inhibitor used for the treatment of postoperative pain. It is known to have anti-platelet properties. The aim of this study was to determine the effect of ketorolac on haemostasis both alone and in combination with low dose heparin in 12 healthy male volunteers. Each volunteer received the following drug combinations in a double blind, placebo controlled, cross over manner: ketorolac placebo/heparin placebo, ketorolac active/heparin placebo, ketorolac active/heparin active and ketorolac placebo/heparin active. Ketorolac significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin cephalin clotting time and increased anti-Xa levels. Ketorolac had no effect on the kaolin cephalin clotting time or anti-Xa levels and no interaction was found between ketorolac and heparin in any of the investigations. The prolongation of bleeding time seen with ketorolac is unlikely, to be of any major clinical significance as almost all subjects remained within the normal range; however, it should be used with caution in subjects with haemostatic problems.     

Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers

Purpose: Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new‐onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated. Methods: Healthy volunteers (n = 119) received atorvastatin 40 mg/day for 7 days followed by addition of lamotrigine (target 300 mg/day) or phenytoin (target ∼4 mg/kg per day) in this open‐label, single‐sequence, two‐cohort study. Serial pharmacokinetic sampling of atorvastatin was conducted on day 7 of atorvastatin dosing and day 70 of lamotrigine + atorvastatin dosing or day 28 of phenytoin + atorvastatin dosing. Main outcome measures were steady‐state area under the curve over the 24‐h dosing interval (AUC_(0–τ)) and maximum concentration (C_max) of atorvastatin and its metabolites, 2OH‐atorvastatin and 4OH‐atorvastatin, in the presence of lamotrigine or phenytoin. Key Findings: When atorvastatin was administered with lamotrigine compared with when atorvastatin was administered alone, atorvastatin AUC_(0–τ) was within bounds indicating no interaction, whereas C_max was slightly higher(14%); AUC_(0–τ) and C_max were 3% and 20% higher, respectively, for 2OH‐atorvastatin and 25% and 21% higher, respectively, for 4OH‐atorvastatin.When atorvastatin was administered with phenytoin compared with when atorvastatin was administered alone, reductions in AUC_(0–τ) and C_max were observed for atorvastatin (54% and 24%, respectively), 2OH‐atorvastatin (53% and 22%, respectively), and 4OH‐atorvastatin (44% and 52%, respectively). Significance: Pharmacokinetics of atorvastatin were not significantly affected by coadministration with lamotrigine. Phenytoin significantly reduced atorvastatin bioavailability. Consistent with the published literature, these data are consonant with the possibility that atorvastatin does not require dose adjustment when coadministered with lamotrigine at doses to 300 mg/day, whereas atorvastatin coadministered with phenytoin may require atorvastatin dose adjustment to maintain atorvastatin exposure.