Long-term effectiveness and safety of edoxaban in patients with atrial fibrillation: 4-year data from the ETNA-AF-Europe study.

BACKGROUND: To assess long-term effectiveness and safety of edoxaban in Europe. METHODS AND RESULTS: ETNA-AF-Europe, a prospective, multinational, multi-centre, post-authorisation, observational study was conducted in agreement with the European Medicines Agency. The primary and secondary objectives assessed real-world safety (including bleeding and deaths) and effectiveness (including stroke, systemic embolic events and clinical edoxaban use), respectively. Median (interquartile range) age of the 13,164 patients was 75.0 (68.0-80.0) years; CHA2DS2-VASc and HAS-BLED scores were 3.0 (2.0-4.0) and 2.0 (1.0-2.0), respectively. Follow-up duration was 3.98 (3.21-4.05) years. Patients on edoxaban 30 mg (n = 3042) at baseline were older (80.0 vs 73.0 years), more likely assessed as frail by investigators (27.0% vs 6.6%) and had more comorbidities than those on edoxaban 60 mg (n = 9617; missing dosing information for n = 505). Annualised event rates of all-cause and cardiovascular death in the overall population, edoxaban 60 mg and edoxaban 30 mg groups were 4.1%, 2.8% and 8.4%, and 1.0%, 0.7% and 2.0%, respectively. Annualised rates of stroke were relatively constant throughout the follow-up, transient ischaemic attack and systemic embolism were < 1% in the overall population. Rates of any major and major gastrointestinal bleeding were low, with slightly higher rates for edoxaban 30 vs 60 mg group. Intracranial haemorrhage was uncommon (0.2%). CONCLUSIONS: In European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding. Differences in outcomes between the two approved doses are attributable to differences in clinical characteristics.

Outcomes after TAVI in patients with atrial fibrillation and a history of recent PCI: Results from the ENVISAGE-TAVI AF trial.

BACKGROUND: Patients with atrial fibrillation (AF) and a recent (≤ 90 days) percutaneous coronary intervention (PCI) undergoing transcatheter aortic valve implantation (TAVI) are at high bleeding risk due to the addition of oral antiplatelet (OAP) agents on top of oral anticoagulants. Data on outcomes of these patients are needed to optimize antithrombotic treatment. METHODS: This analysis compared annualized clinical event rates in patients with and without a recent PCI enrolled in ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban and vitamin K antagonists in AF patients after TAVI. The primary efficacy and safety outcomes were net adverse clinical events (NACE) and major bleeding. RESULTS: Overall, 132 (94.3%) patients with a recent PCI (n = 140) received OAP after TAVI, compared with 692 (55.9%) patients without a recent PCI (n = 1237). Among patients with a recent PCI on OAP agents, use of dual antiplatelet therapy decreased to 5.5%, and use of single antiplatelet therapy (SAPT) increased to 78.0% over 3 months post-randomization. Conversely, use of SAPT predominated at all time points in patients without a recent PCI history. There were no significant differences in the incidence of NACE or other outcomes assessed, except for major bleeding events, which were more frequent in patients with vs without a recent PCI history (hazard ratio [95% confidence interval]: 2.17 [1.27, 3.73]; P = 0.005). CONCLUSIONS: Patients with AF undergoing TAVI with a recent PCI have a similar risk of ischemic events and mortality, but an increased risk of major bleeding compared with patients without a recent PCI.

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

AIMS: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. METHODS AND RESULTS: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. CONCLUSION: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

Clinical risk predictors in atrial fibrillation patients following successful coronary stenting: ENTRUST-AF PCI sub-analysis.

AIMS: This subgroup analysis of the ENTRUST-AF PCI trial (ClinicalTrials.gov Identifier: NCT02866175; Date of registration: August 2016) evaluated type of AF, and CHA2DS2-VASc score parameters as predictors for clinical outcome. METHODS: Patients were randomly assigned after percutaneous coronary intervention (PCI) to either edoxaban (60 mg/30 mg once daily [OD]; n = 751) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist [VKA] (n = 755) plus a P2Y12 inhibitor and aspirin (100 mg OD, for 1-12 months). The primary outcome was a composite of major/clinically relevant non-major bleeding (CRNM) within 12 months. The composite efficacy endpoint consisted of cardiovascular death, stroke, systemic embolic events, myocardial infarction (MI), and definite stent thrombosis. RESULTS: Major/CRNM bleeding event rates were 20.7%/year and 25.6%/year with edoxaban and warfarin, respectively (HR [95% CI]: 0.83 [0.654-1.047]). The event rates of composite outcome were 7.26%/year and 6.86%/year, respectively (HR [95% CI]): 1.06 [0.711-1.587]), and of overall net clinical benefit were 12.48%/year and 12.80%/year, respectively (HR [(95% CI]: 0.99 [(0.730; 1.343]). Increasing CHA2DS2-VASc score was associated with increased rates of all outcomes. CHA2DS2-VASc score ≥ 5 was a marker for stent thrombosis. Paroxysmal AF was associated with a higher occurrence of MI (4.87% versus 2.01%, p = 0.0024). CONCLUSION: After PCI in AF patients, increasing CHA2DS2-VASc score was associated with increased bleeding rates and CHA2DS2-VASc score (≥ 5) predicted the occurrence of stent thrombosis. Paroxysmal AF was associated with MI. These findings may have important clinical implications in AF patients.

Periprocedural anticoagulation in the uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation (ELIMINATE-AF) trial.

AIMS: This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy. METHODS AND RESULTS: Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0-3.0). Uninterrupted anticoagulation was mandated for 21-28 days' pre-ablation and 90 days' post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300-400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1-Q3) time from last dose to ablation procedure was 14.8 (13.3-16.5) vs. 16.5 (14.8-19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU). CONCLUSION: The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.

Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation: a pre-specified analysis of the ENTRUST-AF PCI trial.

AIMS: To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS). METHODS AND RESULTS: In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1-12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59-1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68-1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70-1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47-1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573). CONCLUSIONS: In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation.

Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.

BACKGROUND: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING: Daiichi Sankyo.

Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial.

AIMS: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. METHODS AND RESULTS: The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62). CONCLUSION: Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.

Uninterrupted administration of edoxaban vs vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation: Rationale and design of the ELIMINATE-AF study.

Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non-vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE-AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open-label, parallel-group, blinded-endpoint evaluation (PROBE) study to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation (http://www.ClinicalTrials.gov: NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28 days of anticoagulation prior to the ablation and a 90-day post-ablation period. The primary efficacy endpoint is the composite of all-cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post-ablation. ELIMINATE-AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF.

Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial.

BACKGROUND: The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored. DESIGN: The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis. SUMMARY: The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared.

Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice.

BACKGROUND: Clinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice. METHODS: This multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC. RESULTS: The mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus ≥65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes). CONCLUSION: This study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.

Clinical impact of patient adherence to a fixed-dose combination of olmesartan, amlodipine and hydrochlorothiazide.

BACKGROUND AND OBJECTIVES: Recent findings from randomized clinical trials indicate an improved patient adherence and blood pressure (BP) control by using fixed-dose combinations (FDCs) in the treatment of hypertension. The aim of the present study was to verify those data in a large real-world sample of hypertensive patients and to cross-check adherence evaluation performed by physicians and patients self-assessment. METHODS: A European multi-center, prospective, 24-week, non-interventional study was conducted including 14,979 patients with essential hypertension and new treatment with olmesartan, amlodipine and hydrochlorothiazide as an FDC. Patients' adherence was measured using the Morisky Medication Adherence Scale (MMAS-8) and a non-standardized questionnaire was used by physicians and patients for self-assessment. RESULTS: The mean age of the patients was 63.9±11.78 years and 46.5% were women. One or more cardiovascular risk factors were present in 71.9% of patients and 94.7% had been treated for hypertension before study entry. Mean adherence to medication by MMAS-8 improved from 6.0 to 6.9 at study end. Corresponding improvements of adherence were seen on physicians' and patients' self-assessments throughout the study. Mean decrease of systolic/diastolic BP was 26.4/12.8 mmHg without a relevant difference between the MMAS-8 adherence levels. BP target achievement improved from 55.3 to 67.7% in patients with low versus high adherence. The overall rate of patients with adverse drug reactions was very low (1.76%) but more frequent in patients with low adherence. CONCLUSIONS: Our data confirm previous clinical trial data on the improvement of medication adherence by switching antihypertensive combination therapy to an FDC and a subsequent improvement in BP target achievement. An observed trend toward a reduction in adverse drug reactions needs to be further investigated in clinical trials.

Overweight humans are resistant to the weight-reducing effects of melanocortin4-10.

CONTEXT: By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH(4-10) core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations. OBJECTIVE: The present study aimed to generalize this finding to overweight patients. DESIGN, SUBJECTS, AND INTERVENTION: MSH/ACTH(4-10) (0.5 mg) and placebo were intranasally administered once in the morning and once in the evening over a period of 12 wk in 23 overweight men (body mass index, mean +/- sem: 29.72 +/- 0.43 kg/m(2)). RESULTS: MSH/ACTH(4-10) did not induce any significant reduction in body weight, body fat, and plasma levels of insulin and leptin as compared with the effects of placebo. Melanocortin treatment was accompanied by reduced cortisol concentrations. CONCLUSIONS: We conclude that contrasting with normal-weight humans, overweight subjects are not susceptible to the effects of melanocortin administration on hypothalamic weight regulatory systems. In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal.

Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.

In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.

Brain potential signs of slowed stimulus processing following cholecystokinin in Parkinson's disease.

RATIONALE: Cholecystokinin (CCK) is a neuropeptide which is colocalized with dopamine (DA) in neurons of the mesolimbic-frontocortical and nigrostriatal DA system. In animals CCK enhances DA activity in these systems. OBJECTIVES: The present study examined the effects of a single intranasal administration of CCK-8 on auditory brain potential (AEP) signs of cognitive processing and on motor performance in patients with Parkinson's disease (PD), known to originate from degeneration of DA neurons primarily in the nigrostriatal DA system. METHODS: Thirteen PD patients were examined after medication withdrawal, on two occasions after administration of placebo and 25 microg CCK-8, and compared with healthy controls matched for age and sex. AEPs were recorded while subjects performed an attention task (oddball paradigm). RESULTS: In the placebo condition, AEPs in the PD patients did not show marked alteration but were rather comparable to those in the controls. In healthy controls, CCK-8 enhanced the P3 complex ( P<0.05) and shortened latencies of the N2 and P3 components of the AEP evoked by task relevant target stimuli ( P<0.05). Contrary to expectations, in PD patients these AEP components were distinctly delayed after CCK-8 ( P<0.05). Motor performance was not changed by CCK-8 in PD patients or in controls. CONCLUSION: Data indicate a deleterious rather than beneficial effect of CCK on cognitive processing in PD patients that might result from a prevailing effect of the neuropeptide on transmitter systems (e.g. GABAergic) other than the DA system.