Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial.

OBJECTIVES: Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown. RESEARCH DESIGN AND METHODS: CAMELLIA-TIMI 61 (NCT02019264) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event [MACE]) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years. CONCLUSION: CAMELLIA-TIMI 61 is investigating the safety and efficacy of lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors.

Sistemas de soporte hepático extracorpóreo: [revisión] / Extracorporeal liver support systems: [review]

Introducción. Los sistemas de soporte hepático extracorpóreo (SHE) surgen como una alternativa al trasplante hepático (TH), dado el incremento en la incidencia de falla hepática aguda (FHA), falla hepática crónica agudizada (FHCA), así como las restricciones en la oferta de órganos. Objetivo. Revisión de la literatura de los sistemas de soporte hepático extracorporeo. Metodología. Búsqueda de la literatura publicada entre julio de 1990 y noviembre de 2010 en las principales bases de datos médicas que incluyeron MEDLINE, SciELO y EMBASE, de artículos que analizaran tecnologías relacionadas con sistemas de soporte hepático en cuanto a sus especificaciones técnicas, sus usos y la evidencia respecto a su efectividad en pacientes con algún tipo de falla hepática que requirieran soporte.Resultados. Estos sistemas pueden dividirse en artificiales (hemofiltración, sistema MARS) y bioartificiales (como el Hepatassist™). Su fundamento consiste en reemplazar los procesos de destoxificación relacionados específicamente con el sistema de bilirrubinas, la eliminación de aminoácidos aromáticos, agentes inflamatorios y el manejo de los productos de degradación del sistema de la coagulación. Los recientes avances en bioingeniería y biogenética han hecho que estas tecnologías se acerquen cada vez más a una forma ideal, permitiendo que sean utilizados con relativo éxito en humanos. Los SHE, en su gran mayoría en desarrollo, pretenden no solo actuar como puente al TH, sino que, en casos puntuales, pueden llegar a ser la piedra angular del tratamiento mientras la FHA logra resolverse.

Background. Extracorporeal liver support systems (ELS) have emerged as an alternative to liver transplant (LT), given the growing incidence of acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and the limited organ supply. Objective. Review of literature about Extracorporeal Liver Support Systems. Methodology. A literature search was conducted on the main medical databases including MEDLINE, SciELO and EMBASE for papers published between July 1990 and November 2010 looking at technologies associated with liver support systems, their technical specifications, their use, and evidence regarding their effectiveness in patients with some forms of liver failure requiring support. Results. These systems may be divided into artificial (hemofiltration, MARS) and bioartificial (such as the Hepatassist™). They work by replacing detoxification processes associated specifically with bilirubins, aromatic aminoacids, and inflammatory agents, and the elimination of breakdown products of coagulation. Recent advances in bioengineering and biogenetics have brought these technologies closer to hetheideal, enabling their use in humans with a relative degree of success. ELS systems, most of them still under development, are designed not only to act as a bridge for LT but may also become the cornerstone of treatment in specific cases while the ALF resolves.

Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials.

OBJECTIVE: Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety. METHODS: Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response. RESULTS: Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups. CONCLUSIONS: These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.

Defining treatment response to donepezil in Alzheimer's disease: responder analysis of patient-level data from randomized, placebo-controlled studies.

BACKGROUND: Defining treatment success in progressive diseases, such as Alzheimer's disease (AD), can be challenging. OBJECTIVE: To explore the impact of employing different criteria to define a treatment 'responder' using analyses of patient-level data from randomized, placebo-controlled studies of donepezil in AD. METHODS: Trials were included in the analysis if they met several criteria, including the following: randomized, placebo-controlled trial of donepezil 10 mg/day in mild-to-moderate AD; cognition measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini-Mental State Examination (MMSE); and a 24-week endpoint and outcomes that included global assessments. Definitions of response were: improvements in cognition plus one other domain; improvement in cognition only; improvement or improvement/no change in global response; and improvement/stabilization/less than expected decline by < or = 2 or < or = 4 or < or = 6 points on the ADAS-cog. RESULTS: Five studies identified from the literature search met the specified criteria for inclusion. The response to donepezil measured by ADAS-cog varied from 26% to 63% and that of placebo from 14% to 47%, depending on the definition of improvement used. For definitions that included a less than expected decline on ADAS-cog, the more modest the effect defined, the less the drug versus placebo difference and the higher the percentage of patients meeting this definition. CONCLUSIONS: The definition of treatment 'response' in a progressive neurodegenerative disease can encompass a variety of outcomes, including short-term improvement, longer-term stabilization and a slowed decline in one or more clinically relevant symptoms or symptom domains. The ability to identify groups of people who respond to donepezil underscores the clinical utility of the medication and may contribute to more focused assessments of the cost effectiveness of cholinesterase inhibitors.

Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients.

AIMS: To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady-state, multiple-dose conditions. METHODS: In this single-centre, multiple-dose, open-label study, patients with impaired hepatic function (Child-Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment-emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study. RESULTS: A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in T(max), while t((1/2)) and AUC(0-infinity) were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC(0-24 h), C(max), t((1/2)), C(SS), and R(A) were significantly increased in hepatically impaired patients compared with healthy controls. AUC(0-24 h) increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs. CONCLUSIONS: The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child-Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age-matched volunteers.

Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses.

AIM: This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. METHODS: This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of > or = 3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). RESULTS: A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (< 12%) but statistically significant (P = 0.02) increase in donepezil C(max) was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the t(max) or AUC(0-24 h) of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone. CONCLUSIONS: The co-administration of once-daily oral donepezil HCl 5 mg for 15 days and once-daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed.

Concurrent administration of donepezil HCl and risperidone in patients with schizophrenia: assessment of pharmacokinetic changes and safety following multiple oral doses.

AIM: This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs. METHODS: Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1-4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (C(max), t(max) and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7). RESULTS: The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC(0-24 h) = 329.0 +/- 17.2 ng x h ml(-1)) and controls taking donepezil HCl alone (AUC(0-24 h) = 354.7 +/- 28.2 ng x h ml(-1)). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC(0-12 h) standardized by dose: risperidone = 59.6 +/- 16.3 ng.h ml(-1) at day 0, 56.0 +/- 15.8 ng x h ml(-1) at day 7; 9-OH risperidone = 162.1 +/- 19.2 ng x h ml(-1) at day 0, 163.3 +/- 15.0 ng x h ml(-1) at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration. CONCLUSIONS: These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.

Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia [corrected].

E5564 (alpha-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia.

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.